Xanthine phosphodiesterase V inhibitors

ABSTRACT

A xanthine phosphodiesterase V inhibitor having the formula (I), with the variables defined herein, which is especially useful for treating male (erectile) and female sexual dysfunction and other physiological disorders:  
                 
 
     For example, a representative compound of the invention is:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60,233,567, filed Sep. 19, 2000.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to polycyclic nucleotide xanthinephosphodiesterase V inhibitors.

[0004] 2. Description of Related Art

[0005] Phosphodiesterase (“PDE”) V inhibitor compounds are described byKenneth J. Murray in Phosphodiesterase V _(A) Inhibitors, D N & P 6(3),pp. 150-156 (April, 1993), which is hereby incorporated herein byreference in its entirety, to have potential therapeutic value for anumber of physiological disorders. One compound disclosed in the Murrayarticle is MIMAX, a polycyclic xanthine PDE V inhibitor substituted atits 8-position with a —NHCH₃ group.

[0006] U.S. Pat. No. 5,409,934, which is hereby incorporated herein byreference in its entirety, discloses a series of xanthine PDE Vinhibitors that are substituted at the 8-position with, among otherpossibilities, one of the following groups: —NO₂, —NR^(s)R^(t) or—NR⁶SO₂R⁵, where R^(s) and R^(t), independently of one another, are eacha hydrogen atom or an alkyl group, or R^(s) and R^(t), together with thenitrogen atom to which they are both attached, form a phthalimido group,R⁵ is an alkyl or aryl group, and R⁶ is a hydrogen atom or —SO₂R⁷, whereR⁷ is an alkyl or aryl group.

[0007] U.S. Pat. No. 5,470,579, which is hereby incorporated herein byreference in its entirety, discloses a xanthine PDE V inhibitor having asubstituted or unsubstituted —NH₂ group at the 8-position, for example,—NHR, where R is a C₁-C₆ alkyl group.

[0008] WO 93/23401, which is hereby incorporated herein by reference inits entirety, discloses xanthine PDE V inhibitors that are substitutedat the 8-position with —NH(CH₂)₂CH(CH₂OR⁴)₂.

[0009] WO 92/05176, which is hereby incorporated herein by reference inits entirety, discloses 8-acylaminoxanthine PDE V inhibitors that aresubstituted at the 8-position with —NHCOC₆H₅COOH.

[0010] WO 92/05175, which is hereby incorporated herein by reference inits entirety, discloses 8-aminoxanthine PDE V inhibitors that aresubstituted at the 8-position with —NH₂ or —NHR, where R is an alkyl,arylalkyl or unsaturated heterocyclic (e.g., heteroaryl) group.

[0011] Specific PDE V inhibitors have been found useful for specificindications. For example, the use of PDE V inhibitors for treatingimpotence has met with commercial success with the introduction ofsildenafil citrate, better known as Viagra® (Pfizer, NY, N.Y.). Thechemistry and use of Viagra®, including its mechanism of action intreating erectile dysfunction, are taught in EP 0 702 555 B1, which ishereby incorporated herein by reference in its entirety. Additional PDEV inhibitors useful for treating erectile dysfunction are disclosed inWO 99/24433, which is hereby incorporated herein by reference in itsentirety.

[0012] Erectile dysfunction is a treatable and highly recognized healthconcern, affecting more than 30 million men in the United States,including one in four over age 65. Erectile dysfunction occurs when aman consistently is unable to sustain an erection sufficient forconducting sexual intercourse. In the past, psychological reasons werethe most common explanation for erectile dysfunction or it wasconsidered a natural part of aging. However, researchers todayacknowledge that more than 70 percent of instances of erectiledysfunction are due to physical or medical problems. There are severalfactors that may contribute to erectile dysfunction, including:

[0013] Poor blood circulation—atherosclerosis or hardening of thearteries, high blood pressure and high cholesterol.

[0014] Neurological disorders—multiple sclerosis, Alzheimer's diseaseand Parkinson's disease.

[0015] Hormone imbalances—diabetes, thyroid disorders and lowtestosterone levels.

[0016] Trauma—spinal cord injury, prostate surgery or other trauma tothe pelvic area.

[0017] Prescription and over-the-counter medications—blood pressuremedications, antidepressants and certain drug combinations.

[0018] Lifestyle habits—smoking, alcohol abuse and using illegal drugs.

[0019] U.S. Pat. No. 5,939,419 and U.S. Pat. No. 5,393,755, both ofwhich are hereby incorporated herein by reference in their entirety,disclose polycyclic guanine PDE V derivatives that are useful for thetreatment of cardiovascular and pulmonary disorders.

[0020] As has been shown by the representative art cited above, certainxanthine/guanine PDE V inhibitors have been found to be useful fortreating cardiovascular and pulmonary disorders, while some others havebeen found useful for treating impotence. It has been further shown thatcertain xanthine PDE V inhibitors can be substituted at the 8-positionby a variety of groups, including nitro and unsubstituted or substitutedamino groups. The substituted amino groups include saturatedheterocycles, where the nitrogen atom and its substituents together forman unsaturated heterocyclic group (e.g., —NR^(x)R^(y) can form aheterocycle).

[0021] It is an object of this invention to provide a polycyclicxanthine PDE V inhibitor that possesses beneficial therapeuticproperties.

[0022] It is a further object of the invention to provide a polycyclicxanthine PDE V inhibitor that has especially useful pharmacologicalproperties.

[0023] It is yet another object of the invention to provide a polycyclicxanthine PDE V inhibitor that has good metabolic stability.

[0024] It is still another object of the invention to provide apolycyclic xanthine PDE V inhibitor that is effective for treating avariety of physiological symptoms and diseases in which PDE V plays arole.

[0025] It is also an object of the invention to provide a polycyclicxanthine PDE V inhibitor that is especially effective for treatingerectile dysfunction with minimal side effects.

[0026] These and other objects of the invention will become apparent asthe description progresses.

Definitions and Usage of Terms

[0027] The following definitions and terms are used herein or areotherwise known to a skilled artisan. Except where stated otherwise, thefollowing definitions apply throughout the specification and claims.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “haloalkyl,” “alkoxy,” etc.

[0028] The term “chemically-compatible,” as used herein, means that asubstituent or variable in a structure, process or the like is selectedto be capable of resulting in a stable compound.

[0029] The term “substituted” or the phrase “with . . . one or moresubstituents,” as used herein, means the replacement of one or moreatoms or radicals, usually hydrogen atoms, in a given structure with achemically-compatible atom(s) or radical(s) selected from a specifiedgroup. In the situations where more than one atom or radical may bereplaced with substituents selected from the same specified group, thesubstituents may be, unless otherwise specified, either the same ordifferent at every position. Radicals of specified groups, such asalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl,heterocycloalkyl, aryl and heteroaryl groups, independently of ortogether with one another, may be substituents for any substitutedgroup, unless otherwise known, stated or shown to be to the contrary.

[0030] Representative substituents for alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl andheterocycloalkyl groups include, but are not limited to, the followingmoieties: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl,alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl,aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl,imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di-and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy,halo (e.g., —Cl and —Br), nitro, oximino, —COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰,—SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O,—CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ and—N(R⁵²)CON(R⁵⁰R⁵¹), where:

[0031] R⁵⁰, R⁵¹ and R⁵² may be independently selected from thefollowing: a hydrogen atom and a branched or straight-chain, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₄₋₆ heterocycloalkyl, heteroaryl and aryl group, withor without substituents. When permissible, R⁵⁰ and R⁵¹ can be joinedtogether to form a carbocyclic or heterocyclic ring system. R⁵⁰, R⁵¹ andR⁵² may also include:

[0032] where,

[0033] R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogenatom or a branched or straight-chain, optionally substituted, alkyl,cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl,heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy,aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono-, di- ortrihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino,phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl,alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl,carboxyalkyl, oximino, —COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹,—NR⁵²SO₂R⁵⁰, —CON(R⁵⁰R⁵¹), —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰,—N(R⁵²)CON(R⁵⁰R⁵¹) or —OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵² are asdefined above;

[0034] R⁴² is a hydrogen atom or a branched or straight-chain,optionally substituted, alkyl, alkenyl, arylalkyl or acyl group; and

[0035] R⁴³ is a hydrogen atom or a branched or straight-chain,optionally substituted, alkyl or aryl group;

[0036] wherein, the optional substituents are defined the same as abovefor the one or more substituents.

[0037] Preferred substituents on aryl and heteroaryl groups include, butare not limited to, any of the moieties recited above in the definitionfor R⁴⁰ and R⁴¹.

[0038] The term “heteroatom,” as used herein, means a nitrogen, sulfur,or oxygen atom. Multiple heteroatoms in the same group may be the sameor different.

[0039] The term “hydrocarbon,” as used herein, means a compound orradical consisting of only carbon and hydrogen atoms, includingaliphatic, aromatic, normal, saturated and unsaturated hydrocarbons.

[0040] The term “alkyl,” as used herein, means an unsubstituted orsubstituted, straight or branched, hydrocarbon chain (i.e., comprisingcarbon and hydrogen atoms bonded together), having, preferably, from oneto twenty-four carbon atoms, more preferably, from one to twelve carbonatoms, and most preferably, from one to eight carbon atoms.

[0041] The term “cycloalkyl” or “cycloalkane,” as used herein, means anunsubstituted or substituted, saturated, stable non-aromatic carbocyclicring, having, preferably, from three to fifteen carbon atoms, morepreferably, from three to eight carbon atoms. The carbon ring radical issaturated and may be fused, for example, benzofused, with one to threecycloalkyl, aromatic, heterocyclic or heteroaromatic rings. Thecycloalkyl may be attached at any endocyclic carbon atom that results ina stable structure. Preferred carbocycles have from five to six carbons.Examples of carbocycle radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0042] The term “alkenyl,” as used herein, means an unsubstituted orsubstituted, unsaturated, straight or branched, hydrocarbon chain havingat least one double bond present and, preferably, from two to fifteencarbon atoms, more preferably, from two to twelve carbon atoms.

[0043] The term “cycloalkenyl,” as used herein, means an unsubstitutedor substituted, unsaturated carbocyclic ring having at least one doublebond present and, preferably, from three to fifteen carbon atoms, morepreferably, from five to eight carbon atoms. A cycloalkenyl goup is anunsaturated carbocyclic group. Examples of cycloalkenyl groups includecyclopentenyl and cyclohexenyl.

[0044] The term “alkynyl,” as used herein, means an unsubstituted orsubstituted, unsaturated, straight or branched, hydrocarbon chain havingat least one triple bond present and, preferably, from two to twelvecarbon atoms, more preferably, two to ten carbon atoms.

[0045] The term “bicycloalkyl,” as used herein, represents a saturatedlinearly fused or bridged carbocyclic ring having, preferably, from 5 to12 carbon atoms.

[0046] The term “aryl,” as used herein, means a substituted orunsubstituted, aromatic, mono- or bicyclic carbocyclic ring systemhaving from one to two aromatic rings. The aryl moiety will generallyhave from 6 to 14 carbon atoms with all available substitutable carbonatoms of the aryl moiety being intended as possible points ofattachment. Representative examples include phenyl, tolyl, xylyl,cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Ifdesired, the carbocyclic moiety can be substituted with from one tofive, preferably, one to three moieties, such as mono- throughpentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy,amino, monoalkylamino, dialkylamino and the like.

[0047] The term “heteroaryl,” as used herein, means a mono- or bicyclicring system containing one or two aromatic rings and at least onenitrogen, oxygen or sulfur atom in an aromatic ring. Heteroaryl groups(including bicyclic heteroaryl groups) can be unsubstituted orsubstituted with a plurality of substituents, preferably, one to fivesubstituents, more preferably, one, two or three substituents (e.g.,mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy,alkoxy, phenoxy, amino, monoalkylamino, dialkylamino and the like).Typically, a heteroaryl group represents a cyclic group of five or sixatoms, or a bicyclic group of nine or ten atoms, at least one of whichis carbon, and having at least one oxygen, sulfur or nitrogen atominterrupting a carbocyclic ring having a sufficient number of pi (π)electrons to provide aromatic character. Representative heteroaryl(heteroaromatic) groups are pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, furanyl, benzofuranyl, thienyl, benzothienyl, thiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, isothiazolyl,benzothiazolyl, benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl,1,3,5-triazinyl and indolyl groups.

[0048] The term “arylalkyl,” as used herein, means an alkyl moietysubstituted with an optionally substituted, aryl or heteroaryl group.Representative arylalkyl groups include a benzyl group and fusedbicyclic systems which contain one aryl group.

[0049] The term “alkylaryl,” as used herein, means an aryl or heteroarylmoiety substituted with an optionally substituted, alkyl group.Representative alkylaryl groups include o-, m- and p-linked tolyl andxylyl groups.

[0050] Unless otherwise known, stated or shown to be to the contrary,the point of attachment for a multiple term substituent (multiple termsthat are combined to identify a single moiety) to a subject structure isthrough the last named term of the multiple term. For example, an“arylalkyl” substituent attaches to a targeted structure through the“alkyl” portion of the substituent. Conversely, when the substituent is“alkylaryl”, it attaches to a targeted structure through the “aryl”portion of the substituent. Similarly, a cycloalkylalkyl substituentattaches to a targeted through the latter “alkyl” portion of thesubstituent (e.g., Structure-alkyl-cycloalkyl).

[0051] The term “heterocycloalkyl,” as used herein, means anunsubstituted or substituted, saturated cyclic ring system having fromthree to fifteen members, preferably, from three to eight members, andcomprising carbon atoms and at least one heteroatom as part of the ring.

[0052] The term “heterocyclic ring” or “heterocycle,” as used herein,means an unsubstituted or substituted, saturated, unsaturated oraromatic ring, comprised of carbon atoms and one or more heteroatoms inthe ring. Heterocyclic rings may be monocyclic or polycyclic. Monocyclicrings preferably contain from three to eight atoms, most preferably,five to seven atoms. Polycyclic ring systems consisting of two ringspreferably contain from six to sixteen atoms, most preferably, ten totwelve atoms. Polycyclic ring systems consisting of three rings contain,preferably, from thirteen to seventeen atoms, most preferably, fourteento fifteen atoms. Each heterocyclic ring has at least one hetero atom.Unless otherwise stated, the heteroatoms may be independently selectedfrom the following: nitrogen, sulfur and oxygen atoms.

[0053] The term “carbocyclic ring” or “carbocycle,” as used herein,means an unsubstituted or substituted, saturated, unsaturated oraromatic (e.g., aryl), hydrocarbon ring, unless otherwise specificallyidentified. Carbocycles may be monocyclic or polycyclic. Monocyclicrings preferably contain from three to eight atoms, most preferably,five to seven atoms. Polycyclic rings having two rings preferablycontain from six to sixteen atoms, most preferably, ten to twelve atoms,and those having three rings preferably contain from thirteen toseventeen atoms, most preferably, fourteen to fifteen atoms.

[0054] The term “alkoxy,” as used herein, means an oxygen atom bonded toa hydrocarbon chain, such as an alkyl or alkenyl group (e.g., —O-alkylor —O-alkenyl). Representative alkoxy groups include methoxy, ethoxy,and isopropoxy groups.

[0055] The term “hydroxyalkyl,” as used herein, means a substitutedhydrocarbon chain, preferably, an alkyl group, having at least onehydroxy substituent (i.e., —OH). Additional substituents to the alkylgroup may also be present. Representative hydroxyalkyl groups includehydroxymethyl, hydroxyethyl and hydroxypropyl groups.

[0056] The term “carboxyalkyl,” as used herein, means a substitutedhydrocarbon chain, preferably, a substituted alkyl group, which has acarboxyl substituent (e.g., —COOH) and may also have additionalsubstituents (such as one of the representative substituents identifiedabove for the term “substituted”). Representative carboxyalkyl groupsinclude carboxymethyl (—CH₂CO₂H) and carboxyethyl (—CH₂CH₂CO₂H) groups,and derivatives thereof, such as the corresponding esters.

[0057] The term “aminoalkyl,” as used herein, means an alkyl groupsubstituted with an amine moiety (e.g., -alkylNH₂), such as aminomethyl.

[0058] The term “alkylamino,” as used herein, means an amino moietyhaving from one or two alkyl substituents (e.g., —NH-alkyl), such asdimethylamino.

[0059] The term “alkenylamino,” as used herein, means an amino moietyhaving from one or two alkenyl substituents, where the nitrogen atom ofthe amino group is not attached to the alkene-forming carbon atom (e.g.,—NH—CH₂-alkenyl), such as dibutenylamino.

[0060] The term “arylamino,” as used herein, means an amine moietysubstituted with an aryl group (i.e., —NH-aryl).

[0061] The term “alkylimino,” as used herein, means an imino moietyhaving one alkenyl or two alkyl substituents (e.g., —C═N-alkyl).

[0062] The term “oximino,” as used herein, means compounds containingthe —C═N—OR⁶⁹ radical, where R⁶⁹ is a hydrogen atom or an alkyl or arylgroup.

[0063] The term “aroyl,” as used herein, means the radical R—CO—; whereR is an aromatic group. Representative aroyls are benzoyl and naphthoyl.

[0064] The term “aryloxy,” as used herein, means an oxygen atom havingan aryl substituent (e.g., —O-aryl).

[0065] The term “ester,” as used herein, means compounds containing asubstituted carboxylic acid (e.g., —COO-aryl).

[0066] The term “acyl” or “carbonyl,” as used herein, means a carbon tooxygen double bond, (e.g., R—C(═O)—), which can be a radical of acarboxylic acid having the formula alkyl-CO—, aryl-CO—, arylalkyl-CO—,cycloalkyl-CO—, alkylcycloalkyl-CO— or heteroaryl-CO—. Representativeacyl groups include acetyl, propionyl, butanoyl and benzoyl groups.

[0067] The term “acyloxy,” as used herein, means an oxygen atom havingan acyl substituent (e.g., —O-acyl), for example, —O—C(═O)-alkyl.

[0068] The term “acylamino,” as used herein, means an amino moietyhaving an acyl substituent (e.g., —NH-acyl), for example, an amide withthe formula —NH—(C═O)-alkyl, a urea with the formula —NH—(C═O)—NH-alkylor a carbamate with the formula —NH—(C═O)—OR, where R is an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl orheterocycloalkyl group.

[0069] The term “halo,” “halogen” or “halide,” as used herein, means achloro, bromo, fluoro or iodo atom radical. Chlorides, bromides andfluorides are preferred halides.

[0070] The term “lower hydrocarbon” (e.g., “lower alkyl”), as usedherein, means a hydrocarbon chain comprised of from, unless otherwisestated, one to eight carbon atoms, preferably, one to six carbon atoms,and most preferably, one to four carbon atoms.

[0071] The term “polyhalo,” as used herein, represents substitution ofat least two halo atoms to a group modified by the term “polyhalo.”

[0072] The term “aminosulfonyl,” as used herein, represents a grouphaving the formula: —SO₂NR⁷⁹R⁸⁹, where R⁷⁹ and R⁸⁹ are, independently ofone another, each a hydrogen atom or a lower alkyl (e.g., from 1 to 6carbon atoms) or aryl group.

[0073] The term “sulfonyl,” as used herein, represents a group havingthe formula: —S(O)₂—.

[0074] When a variable appears more than once in a structural formula,for example, R⁵⁹ for where X is —C(OR⁵⁹)₂—, the identity of eachvariable appearing more than once may be independently selected from thedefinition for that variable.

[0075] The term “prodrug,” as used herein, represents a compound that isa drug precursor, which following administration to a patient, releasesa drug in vivo via some kind of chemical and/or physiological process(e.g., a prodrug on being brought to a physiological pH and/or throughan enzyme action is converted to a desired drug form).

[0076] The term “compound of the formula (I.1) or (II.1)”, as usedherein, represents a compound having a chemical structure encompassed bythe formula (I.1) or (II.1), and includes any and all enantiomers,stereoisomers, rotomers, tautomers and prodrugs of the compound.Compounds of the formula (I.1) or (II.1) also include theircorresponding pharmaceutically-acceptable salts, solvates, esters andderivatives.

[0077] The term “pharmaceutically-acceptable excipients,” as usedherein, includes any physiologically inert, pharmacologically inactivematerial known to one skilled in the art, which is compatible with thephysical and chemical characteristics of the particular activeingredient selected for use. Pharmaceutically-acceptable excipientsinclude polymers, resins, plasticizers, fillers, binders, lubricants,glidants, disintegrates, solvents, co-solvents, buffer systems,surfactants, preservatives, sweetening agents, flavoring agents,pharmaceutical grade dyes or pigments, and viscosity agents.

[0078] The term “pharmaceutical composition,” as used herein, means acombination of at least one inventive compound (e.g., PDE V inhibitor)and at least one pharmaceutically-acceptable excipient.

[0079] The terms “compound [having the formula (I)] or a pharmaceuticalcomposition thereof” include neutral, acidic and alkaline forms of thecompound or composition, as well as solvates, esters and salts (as aredefined below) thereof, and further includes derivatives of theinventive compounds.

[0080] The term “pharmaceutically-acceptable salt,” as used herein,means a cationic salt formed at an acidic (e.g., carboxyl) group or ananionic salt formed at a basic (e.g., amino) group of the compound. Manysuch salts are known in the art, for example, those that are describedin WO 87/05297 (1987), which is hereby incorporated in its entirety byreference herein. Preferred cationic salts include the alkali-metalsalts (e.g., sodium and potassium) and alkaline earth metal salts (e.g.,magnesium and calcium). Preferred anionic salts include the halide(e.g., chloride), acetate and phosphate salts.

[0081] The phrase “effective amount,” as used herein, means an amount ofa compound or composition which is sufficient to significantly andpositively modify the symptoms and/or conditions to be treated (e.g.,provide a positive clinical response). The phrase “safe and effectiveamount,” as used herein, means that an “effective amount” must also besafe, that is, an amount that is sufficient to provoke a positiveresponse, yet is small enough to avoid serious side effects (at areasonable benefit/risk ratio), within the scope of sound medicaljudgment. The effective amount of an active ingredient for use in apharmaceutical composition will vary with the particular condition beingtreated, the severity of the condition, the duration of the treatment,the nature of concurrent therapy, the particular active ingredient beingemployed, the particular pharmaceutically-acceptable excipients utilizedand like factors within the knowledge and expertise of the attendingphysician.

[0082] The phrase “administering [to a patient a safe and effectiveamount of the inventive compound],” as used herein, refers to any modeof introducing any form (e.g., solid, liquid or gas) of the inventivecompounds in vivo to a patient (e.g., human or mammal). For example,introduction of the inventive compound to a patient may be accomplishedvia oral ingestion (e.g., tablets, capsules, gels, solutions, etc.),adsorption, absorption (e.g., transmucosal sublingual or buccaladministration), transdermal applications (e.g., topical applicationsvia patches, lotions, etc.), suppositories, etc.

[0083] The term “oral dosage form,” as used herein, means anypharmaceutical composition intended to be systemically administered toan individual by delivering the composition to the gastrointestinaltract of an individual, via the mouth of the individual. For purposes ofthe invention, the delivered form can be a tablet (coated ornon-coated), solution, suspension or capsule (coated or non-coated).

[0084] The term “injection,” as used herein, means any pharmaceuticalcomposition intended to be systemically administered to a human or othermammal, via delivery of a solution or emulsion containing the activeingredient, by puncturing the skin of said individual, in order todeliver the solution or emulsion to the circulatory system of theindividual either by intravenous, intramuscular, intraperitoneal orsubcutaneous injection.

[0085] Other than as shown in the operating examples or where isotherwise indicated, all numbers used in the specification and claimsexpressing quantities of ingredients, reaction conditions, and so forth,are understood as being modified in all instances by the term “about.”

SUMMARY OF THE INVENTION

[0086] The invention comprises a compound having the formula (I):

[0087] where,

[0088] (a) R¹ and R² are, independently of one another, each a C₁₋₁₅alkyl group, branched or straight chain, with or without one or moresubstituents, such as a hydroxy or alkoxy substituent group, a C₂₋₁₅alkenyl group, branched or straight chain, with or without one or moresubstituents, a C₂₋₁₅ alkynyl group, branched or straight chain, with orwithout one or more substituents, a C₃₋₁₅ cycloalkyl group, with orwithout one or more substituents, an arylalkyl group, with or withoutone or more substituents, an aryl group, with or without one or moresubstituents, a heteroaryl group, with or without one or moresubstituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is ahydrogen atom or a hydrocarbon radical, with or without one or moresubstituents, preferably, R⁵ is a hydrogen atom or an alkyl group,branched or straight chain, with or without one or more substituents; or

[0089] one of R¹ and R² is equal to a hydrogen atom, and the other oneof R¹ and R² is defined the same as above;

[0090] (b) R³ is an aryl group, with or without one or moresubstituents, such as a hydroxy or alkoxy substituent group, aheteroaryl group, with or without one or more substituents, or aheterocyclic group having from 1 to 3 heteroatoms fused to a 5- or6-membered aryl ring, with or without one or more substituents, with theproviso that R³ is not an aryl group substituted at its para positionwith a —Y-aryl group, where Y is a carbon-carbon single bond, —CO—, —O—,—S—, —N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—,—NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³)(R²⁴)NH—, —CH═CH—,—CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—,

[0091] where,

[0092] R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,C₃₋₆ cycloalkyl, phenyl or benzyl group;

[0093] R²² is a hydrogen atom or a C₁₋₆ alkyl group;

[0094] R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or —CH₂-aryl group;

[0095] R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group;

[0096] R²⁵ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl, C₃₋₆cycloalkyl, phenyl or benzyl group;

[0097] R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenylor benzyl group;

[0098] R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂,

[0099] and

[0100] R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup or, taken together, a —(CH₂)_(q)— group, where q is 2 or 3;

[0101] Wherein, R²¹ through R²⁹ are with or without one or moresubstituents; and

[0102] (c) R⁴ is a C₃₋₁₅ cycloalkyl group, with or without substituents,such as a hydroxy substituent group, a C₃₋₁₅ cycloalkenyl group, with orwithout one or more substituents, or a heterocycloalkyl group of 3 to 15members, with or without one or more substituents;

[0103] wherein, the optional one or more substituents for all the groupsare chemically-compatible and are, independently of one another, eachdefined the same as recited above in the definition section.

[0104] The invention comprises at least one compound of the formula (I),which includes any and all enantiomers, stereoisomers, rotomers,tautomers and prodrugs of the at least one inventive compound. Compoundsof the formula (I) also include their corresponding salts, solvates(e.g., hydrates), esters, and the like. The invention further comprisespharmaceutically-acceptable compositions prepared from an inventivecompound or a mixture of inventive compounds, or a salt, solvate orester thereof. The compounds of formula (I) can be useful for treating avariety of diseases, symptoms and physiological disorders, such assexual dysfunction, especially impotence (e.g., erectile dysfunction).

[0105] A further understanding of the invention will be had from thefollowing description of preferred embodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0106] The inventive compounds having the formula (I) are substituted atthe 8-position on the chemical structure with an amino group that itselfis substituted with one of the following groups: an unsaturated orsaturated carbocyclic group and a saturated heterocyclic group. Theinventive substituted xanthines exhibited unexpectedly enhancedproperties with respect to enzyme activity and enzyme selectivity. It isbelieved that the substitution at the 8-position of the subject PDE Vinhibitor compounds with these specific groups, helped produceunexpectedly highly potent and selective xanthines, which exhibitedincreased isozyme selectivity when compared to conventional xanthines.Pharmaceutical compositions comprising the inventive compounds possessunexpectedly superior therapeutic properties.

[0107] Referring above to the inventive xanthine PDE V inhibitorcompounds having the formula (I), the 8-position on the chemicalstructure is substituted with a —NHR⁴ group, where R⁴ represents acarbocyclic or heterocyclic system defined as follows: a C₃₋₁₅cycloalkyl group, a C₃₋₁₅ cycloalkenyl group or a heterocycloalkyl groupof 3 to 15 members. All of the cyclic systems are optionallysubstituted. Preferred substituents on the cyclic systems include a C₃₋₆cycloalkyl group, a C₁₋₆ alkoxy C₁₋₆ alkyl group, a C₁₋₆ alkyl group, anamino C₁₋₆ alkyl group, a C₁₋₆ dialkylamino C₁₋₆ alkyl group, a C₃₋₆dicycloalkylamino C₁₋₆ alkyl group, a hydroxy group, an alkoxy group, anoximino group, —COR⁶, —SO₂R⁶, —COOR⁶, —CONR⁶R⁷, —SO₂NR⁶R⁷, —N(R⁸)SO₂R⁶and —NR⁶R⁷, where:

[0108] R⁶ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl group;

[0109] R⁷ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl group; or

[0110] R⁶ and R⁷, when applicable, may be joined together to form aheterocyclic ring system; and

[0111] R⁸ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl group.

[0112] Furthermore, R⁴ may also be substituted with -ZR⁷⁰Z′-, where R⁷⁰,together with Z and Z′, form a spiro-fused 5- to 7-membered ring or alinearly fused 4- to 7-membered ring system, and Z and Z′, independentlyof one another, are each an oxygen, sulfur or nitrogen atom. Forexample, when Z=Z′=O, R⁴ may be substituted by the following structurehaving the formula (VIII):

[0113] Preferred substituents are defined above for the groups. Othersubstituents may also be used, such as ketones, oximes, cyclic systems,including lineraly fused and bridged, mono-, bi- and tricyclic rings,spiro-cyclic systems, including ketals and thioketals directly attachedto R⁴, halogens and sulfonamides. One skilled in the art can determineother possible substituents depending on the conditions employed and thedesired properties.

[0114] A preferred structure of the invention is represented by formula(II):

[0115] where,

[0116] R¹, R² and R³ are defined the same as above for the compound offormula (I);

[0117] R⁹ is one of the following atoms or groups:

[0118] (a) a hydrogen atom;

[0119] (b) an oximino group;

[0120] (c) a carboxyalkyl group;

[0121] (d) a C₁₋₆ alkoxy C₁₋₆ alkyl group;

[0122] (e) an aryloxy C₁₋₆ alkyl group;

[0123] (f) a C₃₋₆ cycloalkoxy C₁₋₆ alkyl group;

[0124] (g) a heteroaryloxy C₁₋₆ alkyl group;

[0125] (h) a —COOH group;

[0126] (i) an ester group;

[0127] (j) a C₁₋₆ alkyl group;

[0128] (k) a C₃₋₆ cycloalkyl group;

[0129] (l) a C₃₋₆ heterocyclic group;

[0130] (m) a hydroxy C₁₋₆ alkyl group;

[0131] (n) an aryl group; or

[0132] (o) a heteroaryl group;

[0133] wherein, all of the above groups are optionally substituted;

[0134] R¹⁰ and R¹¹ are substituents on the same or different carbonatoms of the ring and, independently of one another, are each definedthe same as above for R⁹ and, additionally, may each be one of thefollowing groups:

[0135] (a) a hydroxy group;

[0136] (b) an ester group derived from a hydroxy group with a:

[0137] (i) C₁₋₆ carboxylic acid;

[0138] (ii) C₃₋₆ cycloalkyl C₁₋₆ carboxylic acid;

[0139] (iii) aryl C₁₋₆ carboxylic acid; or

[0140] (iv) heteroaryl C₁₋₆ carboxylic acid group;

[0141] (c) a C₁₋₆ alkoxy group;

[0142] (d) an amino group;

[0143] (e) a C₁₋₆ mono- or dialkylamino group;

[0144] (f) a C₁₋₆ alkylacylamino group;

[0145] (g) a C₁₋₆ alkylsulfonylamino group; or

[0146] (h) a —NHCON(R¹⁴)₂ group, where R¹⁴ is a hydrogen atom or anoptionally substituted, alkyl or aryl group; or

[0147] R¹⁰ and R¹¹, taken together with each other and, optionally, withone or more carbon and/or hetero atoms of the ring, form an optionallysubstituted, spiro-fused, linearly fused, bi- or tri-cyclic ring systemof from 8 to 12 members, including from 0 to 4 hetero atoms, where, allof the above R¹⁰, R¹¹ and R¹⁴ groups are optionally substituted;

[0148] m and n are, independently of one another, each from 1 to 3; and

[0149] X is a chemcially-compatible group, which is —C(R¹⁰R¹¹)—,—S(O)_(y), —O—, —N(R⁶⁰)—, where:

[0150] R¹⁰ and R¹¹ are, independently of one another, each defined thesame as previously;

[0151] y is from 0 to 2;

[0152] R⁶⁰ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl, C₁₋₈alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, C₄₋₈ heterocycloalkyl,COR⁶¹, SO₂R⁶¹, COOR⁶¹, CONR⁶¹R⁶² or SO₂NR⁶¹R⁶² group, with or withoutsubstituents, where:

[0153] R⁶¹ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl, C₁₋₈alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl or C₄₋₈ heterocyclic group,with or without substituents;

[0154] R⁶² is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl, C₁₋₈alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl or C₄₋₈ heterocyclic group,with or without substituents; and

[0155] when R⁶¹ and R⁶² are (the same or different) alkyl groups, theycan, if desired, be joined together to form a carbocyclic orheterocyclic ring system;

[0156] wherein, the optional substituents and the one or moresubstituents are defined the same as for the one or more substituents offormula (I) above.

[0157] In the compound of formula (II), the different carbon atoms towhich R¹⁰ and R¹¹ may be connected can be adjacent or non-adjacent.Preferably, R⁹, R¹⁰ and R¹¹ are all hydrogen atoms. In anotherembodiment of the invention, one of R¹⁰ or R¹¹ is, advantageously, ahydroxy group.

[0158] In the compounds of formulas (I) and (II), R¹ is, preferably, analkyl group or an arylalkyl group, particularly, a benzyl group. Morepreferably, R¹ is a lower alkyl group of from 1 to 4 carbon atoms, andmost preferably, a methyl or ethyl group.

[0159] R², in the compounds of formulas (I) and (II), is, preferably, analkyl group, particularly, an alkyl group substituted with a hydroxygroup. More preferably, R² is a lower alkyl group of from 1 to 3 carbonatoms or a hydroxyalkyl group, and most preferably, R² is a methyl,ethyl, iso-butyl or hydroxyethyl group.

[0160] In the compounds of formulas (I) and (II), R³ is, preferably, anaryl group, particularly, an aryl group substituted with a hydroxy-,alkoxy- or amino-sulfonyl group, which may be, advantageously,substituted with 1 or 2 halogen atoms. When R³ is a heteroaryl group inthe compounds of formulas (I) and (II), it is generally preferable toutilize heteroaryl groups other than furan. Most preferably, R³ is amethoxyaryl group substituted on its aryl ring with at least one halogenatom, for example, a substitution with 1 or 2 halogen atoms, such aschlorine or bromine. For instance, R³ can be 4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl, 4-methoxyphenyl,3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-aminosulfonylphenylgroup, 3-chloro-4-aminosulfonylphenyl group or3-bromo-4-aminosulfonyl-phenyl.

[0161] R⁴, in the compound of formula (I), is, preferably, a cycloalkylor heterocycloalkyl group, particularly, a cycloalkyl group substitutedwith a hydroxy group. More preferably, R⁴ is a cyclohexyl,hydroxycyclopentyl or tetrahydropyranyl group. Most preferably, R⁴ is ahydroxycyclopentyl group. For instance, R⁴ can be a2(R)-hydroxy-1(R)-cyclopentyl group. All of the preferred embodimentsmay be unsubstituted or substituted.

[0162] The compounds of formulas (I) and (II) are useful for treatingurogenital diseases, such as male (e.g., impotence/erectile dysfunction)and female sexual dysfunction. The following compounds listed in TablesI and II are illustrative of the invention: TABLE I Compound No.Structure 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

[0163] TABLE II Compound No. STRUCTURE HRMS Calc. HRMS Found M, M + 1100

439.2821 439.2821 (M + 1) 101

412.2349 412.2346 (M + 1) 102

526.3213 526.3203 (M+) 103

442.2454 442.2451 (M + 1) 104

428.2298 428.2294 (M + 1) 105

476.2065 476.2057 (M + 1) 106

478.1857 478.1851 (M + 1) 107

462.1908 462.191 (M + 1) 108

490.1857 490.1853 (M + 1) 109

492.1650 492.1641 (M + 1) 110

455.2533 455.2518 (M+) 111

458.2403 458.2395 (M + 1) 112

442.2454 442.2448 (M + 1) 113

444.2247 444.2252 (M + 1) 114

522.1352 522.1346 (M + 1) 115

464.1701 464.1696 (M + 1) 116

506.1403 506.141 (M + 1) 117

520.1559 520.1568 (M + 1) 118

508.1196 508.119 (M + 1) 119

475.2128 475.2134 (M + 1) 120

429.1932 429.1931 (M+) 121

488.2332 488.2333 (M + 1) 122

504.1610 504.1605 (M + 1) 123

506.1403 506.1395 (M + 1) 124

522.1542 522.1542 (M + 1) 125

520.1559 520.1552 (M + 1) 126

477.1920 477.1919 (M + 1) 127

477.1920 477.1914 (M + 1) 128

536.1335 536.1335 (M + 1) 129

522.1352 522.136 (M + 1) 130 no structure n/a n/a n/a 131

382.2243 382.2242 (M + 1) 132

382.2243 382.2238 (M + 1) 133

424.2713 424.2717 (M + 1) 134

396.2400 396.2396 (M + 1) 135

396.2400 396.2393 (M + 1) 136

386.1992 386.1988 (M + 1) 137

386.1992 386.1988 (M + 1) 138

386.1992 386.1985 (M + 1) 139

398.2192 398.2196 (M + 1) 140

382.2243 382.2238 (M + 1) 141

398.2192 398.2192 (M + 1) 142

412.1985 412.1982 (M + 1) 143

428.2298 428.2294 (M + 1) 144

412.2349 412.2346 (M + 1) 145

384.2036 384.2041 (M + 1) 146

384.2036 384.2033 (M + 1) 147

398.2192 398.2184 (M + 1) 148

402.1697 402.1691 (M + 1) 149

493.0975 493.098 (M+) 150

451.1831 451.1819 (M+) 151

435.1882 435.1879 (M+) 152

446.1192 446.1187 (M + 1) 153

435.1229 435.1219 (M+) 154

404.1898 404.1895 (M + 1) 155

428.2298 428.2292 (M + 1) 156

420.1603 420.1603 (M + 1) 157

413.1937 413.1932 (M + 1) 158

444.2400 444.2394 (M + 1) 159

431.1724 431.173 (M+) 160

446.1595 446.1588 (M + 1) 161

418.1646 418.164 (M + 1) 162

436.1960 436.1962 (M + 1) 163

436.1960 436.1957 (M + 1) 164

452.1909 452.1919 (M + 1) 165

414.2305 414.2303 (M + 1) 166

440.2662 440.2657 (M + 1) 167

426.2505 426.2509 (M + 1) 168

440.2298 440.2295 (M + 1) 169

426.2505 426.2498 (M + 1) 170

412.2349 412.2345 (M + 1) 171

474.2272 474.2277 (M + 1) 172

459.2037 459.2055 (M+) 173

428.2462 428.2457 (M + 1) 174

440.2662 440.2657 (M + 1) 175

454.2454 454.2449 (M + 1) 176

454.2818 454.2812 (M + 1) 177

426.2505 426.2503 (M + 1) 178

440.2662 440.2666 (M + 1) 179

509.1738 509.1729 (M + 1) 180

555.1233 555.123 (M + 1) 181

511.153 511.1524 (M + 1) 182

491.2077 491.2087 (M + 1) 183

525.1687 525.1697 (M + 1) 184

571.1164 571.1138 (M + 1) 185

538.1492 538.1498 (M + 1) 186

524.1335 524.1344 (M + 1) 187

575 575 (M) LRMS 188

477.192 477.1919 (M + 1) 189

477.192 477.1919 (M + 1) 190

557.1007 557.0997 (M + 1) 191

511.153 511.1519 (M + 1) 192

494.1637 494.1636 (M + 1) 193

510.1578 510.1574 (M + 1) 194

554.1073 554.1066 (M + 1) 195

525.159 525.1582 (M + 1) 196

525.159 525.1597 (M + 1) 197

478.168 478.1683 (M + 1) 198

522.1174 522.1169 (M + 1) 199

542.1405 542.143 (M + 1)

[0164] The compounds of the invention are useful for inhibiting PDE Venzymes. Their enzyme activities and enzyme selectivities can beevaluated in a number of ways. In particular, enzyme activity can bemeasured by the PDE V IC₅₀ value, which is the concentration (in nM) ofthe compound required to provide 50% inhibition of PDE V. The lower thevalue of IC₅₀, the more active is the compound. Measurements on thecompounds in Tables I and II gave the following data (all numbers aremodified by the word “about”):

[0165] A. all compounds had a PDE V IC₅₀ within the range of from <1 nMto >100 nM;

[0166] B. compound nos. 13-18, 25, 30-32, 38, 41-43, 55-58, 69-71, 77,85, 92, 96, 98, 101, 113, 120, 121, 126, 128, 131, 137, 138, 141,146-48, 165, 166, 173, 176, 181, 182, 184, 185, 193 and 194 had a PDE VIC₅₀ within the range of from >15 to 100 nM;

[0167] C. compound nos. 23, 24, 29, 33, 34, 39, 40, 93, 94, 108, 111,112, 125, 136, 144, 160 and 161 had a PDE V IC₅₀ within the range offrom >10 to 15 nM.

[0168] D. compound nos. 21, 22, 28, 36, 37, 59, 66, 68, 78, 79, 89, 95,99, 110, 115, 132, 159, 171, 172, 175, 180, 183, 190 and 199 had a PDE VIC₅₀ within the range of from >5 to 10 nM; and

[0169] E. compound nos. 60-65, 67, 103-07, 114, 116-19, 122-24, 142,168-70, 177, 178, 179, 186-88, 191, 197 and 198 had a PDE V IC₅₀ withinthe range of up to 5 nM.

[0170] In addition, another type of measurement that can be made is theratio of PDE VI IC₅₀/PDE V IC₅₀ (identified as “PDE VI/PDE V”), which isan indicator of enzyme selectivity—the higher the ratio, the moreselective is the compound to inhibiting PDE V enzyme relative to PDE VIenzyme. Measurements on the compounds (except for compound nos. 189,192, 195 and 196) in Table II gave the following data (all numbers aremodified by the word “about”):

[0171] F. compound nos. 1-188, 190, 191, 193, 194 and 197-99 had a PDEVI/PDE V ratio of >0;

[0172] G. compound nos. 165 and 193 had a PDE VI/ PDE V ratio within therange of from >0 to 10;

[0173] H. compound nos. 101, 108, 136, 141, 146, 148, 168, 173 and 194had a PDE VI/ PDE V ratio within the range of from >10 to 25;

[0174] I. compound nos. 104, 125, 131-32. 137-38, 142, 144, 170, 175,177, 185 and 199 had a PDE VI/PDE V ratio within the range of from >25to 50;

[0175] J. compound nos. 103, 110, 111, 117, 159, 166, 182 and 187 had aPDE VI/PDE V ratio within the range of from >50 to 75;

[0176] K. compound nos. 105, 106, 147 and 171 had a PDE VI/PDE V ratiowithin the range of from >75 to 100;

[0177] L. compound nos. 112, 113, 123, 124, 126, 169, 172 and 184 had aPDE VI/PDE V ratio within the range of from >100 to 140; and

[0178] M. compound nos. 107, 114-16, 118-22, 128, 160-61, 176, 178-81,183, 186, 188, 190, 191, 197 and 198 had a PDE VI/PDE V ratio of from>140.

[0179] Preferred compounds of the invention include those found inclasses E and/or M: compound nos. 60-65, 67, 103-07, 114-24, 128, 142,160-61, 168-70, 176-78, 179, 186, 188, 191, 197 and 198. More preferredcompounds of the invention are compound nos. 107, 114, 116, 118, 119,122, 160, 178 and 186 of Table II.

[0180] Another preferred compound of the invention would have thefollowing chemical structure:

[0181] Specific and general procedures for producing three preferredcompounds follow below (compound nos. 107, 114 and 160). Obviousmodifications to these procedures may be undertaken by one of ordinaryskill in the art. Other compounds of the invention may be produced alongthe same lines.

[0182] Synthesis of Compound No. 107 in Table II (7)

[0183] Preparation of 9

[0184] Experimental Procedure: Compound No. 107 in Table II (7)

[0185] 1 (20.0 g, 74.0 mmol) was dissolved in dimethylformamide (370 mL)under nitrogen and (2-bromoethoxy)-tert-butyldimethylsilane (31.8 mL,148 mmol) was added dropwise. The reaction was stirred at roomtemperature for 115 hrs., then diluted with ethyl acetate and washedwith water several times. The organic mixture was dried over potassiumcarbonate, filtered and concentrated under vacuum. Purification viaflash chromatography (30/70 ethyl acetate/hexanes) yielded 2 (28.1 g,88%).

[0186]¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.29-7.39 (m, 5H), 5.49(s, 2H), 4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H,J=6.0 Hz), 1.24 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS:Calcd for C₂₂H₃₂N₄O₃Si (M+H): 429.2322. Found: 429.2329.

[0187] To a solution of 2 (2.10 g, 4.89 mmol) in methanol (375 mL) wasadded ammonium formate (4.64 g, 73.6 mmol) and 20% palladium hydroxideon carbon (980 mg). The reaction was heated to reflux for 1.5 hrs., thencooled to room temperature, filtered and concentrated under vacuum.Purification via flash chromatography (50/50 ethyl acetate/hexanes)yielded 3 (1.26 g, 94%).

[0188]¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 1H), 4.33 (t, 2H, J=6.0 Hz),4.16 (q, 2H, J=7.2 Hz), 3.99 (t, 2H, J=6.0 Hz), 1.29 (t, 3H, J=7.2 Hz),0.78 (s, 9H), 0.06 (s, 6H). HRMS: Calcd for C₁₅H₂₆N₄O₃Si (M+H):339.1852. Found: 339.1864.

[0189] To 3 (970 mg, 2.86 mmol) was added dimethylformamide (14 mL),3-chloro-4-methoxybenzyl bromide 9 (1.72 g, 5.70 mmol), and potassiumcarbonate (785 mg, 5.70 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 24 hrs., then diluted with ethyl acetateand washed with water several times. The organic mixture was dried overpotassium carbonate, filtered and concentrated under vacuum.Purification by flash chromatography (30/70 ethyl acetate/hexanes)yielded 4 (1.14 g, 81%).

[0190]¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.33 (d, 1H, J=2.4 Hz),7.25 (dd 1H, J=2.0 Hz, J=8.4 Hz), 6.90 (d, 1H, J=8.8 Hz), 5.40 (s, 2H),4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.0 Hz),3.89 (s, 3H), 1.25 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS:Calcd for C₂₃H₃₃ClN₄O₄Si (M+H): 493.2038. Found: 493.2032.

[0191] To solution of 4 (1.14 g, 2.32 mmol) in tetrahydrofuran (20 mL)under nitrogen at −78° C. (dry ice/acetone bath) was added lithiumdiisopropylamide (2M in THF/heptane, 1.7 mL, 3.48 mmol). After stirringfor thirty minutes, 1,2-dibromotetrafluoroethane (0.55 mL, 4.63 mmol)was added dropwise over five minutes. The reaction was stirred for 1.5hrs. at −78° C. then quenched with saturated aqueous sodium bicarbonateand warmed to room temperature. The mixture was extracted withdichloromethane, dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 5 (640 mg, 48%).

[0192]¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, 1H, J=2.4 Hz), 7.31 (dd, 1H,J=2.0 Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.8 Hz), 5.45 (s, 2H), 4.22 (t, 2H,J=5.6 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.92 (t, 2H, J=5.6 Hz), 3.88 (s, 3H),1.25 (t, 3H, J=7.2 Hz), 0.74 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₃H₃₂BrClN₄O₄Si (M+H): 571.1143. Found: 571.1149.

[0193] To 5 (320 mg, 0.56 mmol) was added cyclohexylamine (0.25 mL, 2.24mmol), diisopropylethylamine (2.8 mL), and 1-methyl-2-pyrrolidinone (2.8mL). The reaction mixture was heated to 160° C. in a sealed tube for 18hrs., then cooled to room temperature. Water was added, then the mixturewas extracted with ethyl acetate and washed with water several times.The organic mixture was dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 6 (210 mg, 64%).

[0194]¹H NMR (400 MHz, CDCl₃): δ 7.27 (d, 1H, J=2.0 Hz), 7.13 (dd, 1H,J=2.0 Hz, J=8.4 Hz), 6.89 (d, 1H, J=8.8 Hz), 5.23 (s, 2H), 4.19 (t, 2H,J=6.2 Hz), 4.05 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.2 Hz), 3.89 (s, 3H),3.86-3.91 (m, 1H), 3.69-3.80 (m, 1H), 1.88-1.96 (m, 2H), 1.52-1.64 (m,3H), 1.28-1.42 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.04-1.22 (m, 3H), 0.81(s, 9H), 0.01 (s, 6H). HRMS: Calcd for C₂₉H₄₄ClN₅O₄Si (M+H): 590.2937.Found: 590.2929.

[0195] 6 (191 mg, 0.324 mmol) was dissolved in dichloromethane (4.0 mL)under nitrogen and cooled to 0° C. in an ice bath. Boron tribromide(0.14 mL, 1.42 mmol) was added to the reaction mixture and warmed toroom temperature. After 1.25 hr., the reaction was diluted withdichloromethane and washed with water several times. The organic phasewas dried over potassium carbonate, filtered and concentrated undervacuum. Purification via PTLC (70/30 ethyl acetate/hexanes) yielded 7(compound no. 107 in Table II) (122 mg, 74%).

[0196]¹H NMR (400 MHz, CDCl₃): δ 7.25-7.28 (m, 1H), 7.09 (dd, 1H, J=2.0Hz, J=8.0 Hz), 7.01 (d, 1H, J=8.0 Hz), 5.69 (s, 1H), 5.23 (s, 2H),4.32-4.36 (m, 2H), 4.16 (t, 1H, J=6.0 Hz), 4.06 (q, 2H, J=7.2 Hz),3.90-3.98 (m, 3H), 3.62-3.72 (m, 1H), 1.87-1.96 (m, 2H), 1.54-1.66 (m,3H), 1.31-1.43 (m, 2H), 1.25 (t, 3H, J=7.2 Hz), 1.06-1.22 (m, 3H). HRMS:Calcd for C₂₂H₂₈ClN₅O₄ (M+H): 462.1908. Found: 462.1901.

[0197] 3-Chloro-4-methoxytoluene 8 (2.6 mL, 19.2 mmol) was dissolved indichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 21.1 mmol) wasadded followed by AIBN (36.0 mg). The reaction was heated to reflux for19 hrs., then cooled to room temperature and the precipitate wasfiltered off. The filtrate was diluted with dichloromethane and washedwith 0.5 M aqueous sodium bicarbonate, followed by water. The organicmixture was dried over sodium sulfate, filtered and concentrated undervacuum to yield 9 (4.73 g, 82%). The benzyl bromide was used as thecrude material without further purification.

[0198]¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, 1H, J=2.4 Hz), 7.26 (dd, 1H,J=2.4 Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.4 Hz), 4.44 (s, 2H), 3.90 (s, 3H).

[0199] General Synthesis of Compound No. 107 in Table II (7)

[0200] a) Reacting 1 with an alkyl halide and base to form 2;

[0201] b) Debenzylation of 2 to form 3;

[0202] c) Alkylation of 3 with a benzyl halide to form 4;

[0203] d) Deprotonation of 4 followed by addition of a brominating agentto form 5;

[0204] e) Displacement of bromo 5 with an amine to form 6; and

[0205] f) Treatment of 6 with boron tribromide to form compound no. 107in Table II (7) via cleavage of both silyl and methyl ethers.

[0206] Synthesis of Compound 114 in Table II (13)

[0207] Preparation of 15

[0208] Experimental Procedure: Compound 114 in Table II (13)

[0209] 1 (20.0 g, 74.0 mmol) was dissolved in dimethylformamide (370 mL)under nitrogen and (2-bromoethoxy)-tert-butyldimethylsilane (31.8 mL,148 mmol) was added dropwise. The reaction was stirred at roomtemperature for 115 hrs., then diluted with ethyl acetate and washedwith water several times. The organic mixture was dried over potassiumcarbonate, filtered and concentrated under vacuum. Purification viaflash chromatography (30/70 ethyl acetate/hexanes) yielded 2 (28.1 g,88%).

[0210]¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.29-7.39 (m, 5H), 5.49(s, 2H), 4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H,J=6.0 Hz), 1.24 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS:Calcd for C₂₂H₃₂N₄O₃Si (M+H): 429.2322. Found: 429.2329.

[0211] To a solution of 2 (2.10 g, 4.89 mmol) in methanol (375 mL) wasadded ammonium formate (4.64 g, 73.6 mmol) and 20% palladium hydroxideon carbon (980 mg). The reaction was heated to reflux for 1.5 hrs., thencooled to room temperature, filtered and concentrated under vacuum.Purification via flash chromatography (50/50 ethyl acetate/hexanes)yielded 3 (1.26 g, 94%).

[0212]¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 1H), 4.33 (t, 2H, J=6.0 Hz),4.16 (q, 2H, J=7.2 Hz), 3.99 (t, 2H, J=6.0 Hz), 1.29 (t, 3H, J=7.2 Hz),0.78 (s, 9H), 0.06 (s, 6H). HRMS: Calcd for C₁₅H₂₆N₄O₃Si (M+H):339.1852. Found: 339.1864.

[0213] To 3 (970 mg, 2.86 mmol) was added dimethylformamide (25 mL),3-bromo-4-methoxybenzyl bromide 15 (1.62 g, 5.79 mmol), and potassiumcarbonate (800 mg, 5.79 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 21 hrs., then diluted with ethyl acetateand washed with water several times. The organic mixture was dried overpotassium carbonate, filtered and concentrated under vacuum.Purification by flash chromatography (30/70 ethyl acetate/hexanes)yielded 10 (1.55 g, 100%).

[0214]¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.51 (d, 1H, J=2.4 Hz),7.30 (dd 1H, J=2.0 Hz, J=8.4 Hz), 6.87 (d, 1H, J=8.8 Hz), 5.40 (s, 2H),4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.0 Hz), 3.93 (t, 2H, J=6.0 Hz),3.88 (s, 3H), 1.25 (t, 3H, J=7.0 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS:Calcd for C₂₃H₃₃BrN₄O₄Si (M+H): 537.1533. Found: 537.1540.

[0215] To solution of 10 (1.50 g, 2.80 mmol) in tetrahydrofuran (24 mL)under nitrogen at −78° C. (dry ice/acetone bath) was added lithiumdiisopropylamide (2M in THF/heptane, 2.2 mL, 4.33 mmol). After stirringfor thirty minutes, 1,2-dibromotetrafluoroethane (0.69 mL, 5.77 mmol)was added dropwise over five minutes. The reaction was stirred for 1.25hrs. at −78° C. then quenched with saturated aqueous sodium bicarbonateand warmed to room temperature. The mixture was extracted withdichloromethane, dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 11 (600 mg, 34%).

[0216]¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H,J=2.0 Hz, J=8.4 Hz), 6.84 (d, 1H, J=8.4 Hz), 5.45 (s, 2H), 4.21 (t, 2H,J=5.6 Hz), 4.07 (q, 2H, J=6.8 Hz), 3.90 (t, 2H, J=5.6 Hz), 3.87 (s, 3H),1.24 (t, 3H, J=6.8 Hz), 0.73 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₃H₃₂Br₂N₄O₄Si (M+H): 615.0638. Found: 615.0633.

[0217] To 11 (1.89 g, 3.07 mmol) was added the amino alcoholhydrochloride salt (1.31 g, 12.27 mmol), diisopropylethylamine (15.4mL), and 1-methyl-2-pyrrolidinone (15.4 mL). The reaction mixture washeated to 160° C. in a sealed tube for 13 hrs., then cooled to roomtemperature. Water was added, then the mixture was extracted with ethylacetate and washed with water several times. The organic mixture wasdried over potassium carbonate, filtered and concentrated under vacuum.Purification via flash chromatography (3/97 methanol/dichloromethane)yielded 12 (1.77 g, 90%).

[0218]¹H NMR (400 MHz, CDCl₃): δ 7.45 (d, 1H, J=2.0 Hz), 7.17 (dd, 1H,J=2.4 Hz, J=8.6 Hz), 6.86 (d, 1H, J=8.4 Hz), 5.18-4.34 (m, 3H),4.00-4.23 (m, 5H), 3.86-3.98 (m, 6H), 3.69-3.79 (m, 1H), 2.10-2.21 (m,1H), 1.99-2.10 (m, 1H), 1.60-1.84 (m, 3H), 1.32-1.43 (m, 1H), 1.24 (t,3H, J=7.2 Hz), 0.75 (s, 9H), 0.07 (d, 6H, J=4.0 Hz). HRMS: Calcd forC₂₈H₄₃BrN₅O₅Si (M+H): 636.2217. Found: 636.2207.

[0219] 12 (1.77 g, 2.78 mmol) was dissolved in tetrahydrofuran (28 mL)under nitrogen and tetrabutylammonium fluoride (1M in THF, 28 mL) wasadded dropwise. The reaction was stirred at room temperature for 15hrs., then diluted with dichloromethane and washed with water severaltimes. The organic mixture was dried over potassium carbonate, filteredand concentrated under vacuum. Purification via flash chromatography(3/97 methanol/dichloromethane) yielded 13 (compound no. 114 in TableII) (760 mg, 52%).

[0220]¹H NMR (400 MHz, CDCl₃): δ 7.47 (d, 1H, J=2.0 Hz), 7.19 (dd, 1H,J=2.0 Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.4 Hz), 5.25 (s, 2H), 5.09 (s, 1H),4.21-4.27 (m, 3H), 4.06 (q, 2H, J=7.0 Hz), 3.90-3.97 (m, 3H), 3.89 (s,1H), 3.74-3.82 (m, 1H), 3.08 (s, 1H), 2.12-2.22 (m, 1H), 1.98-2.08 (m,1H), 1.60-1.86 (m, 3H), 1.33-1.43 (m, 1H), 1.25 (t, 3H, J=7.0 Hz),1.06-1.22 (m, 3H). HRMS: Calcd for C₂₂H₂₈BrN₅O₅ (M+H): 522.1352. Found:522.1346.

[0221] 2-Bromo-4-methyl anisole 14 (2.2 mL, 14.9 mmol) was dissolved indichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 16.4 mmol) wasadded followed by AIBN (26.0 mg). The reaction was heated to reflux for19 hrs., then cooled to room temperature and the precipitate wasfiltered off. The filtrate was diluted with dichloromethane and washedwith 0.5 M aqueous sodium bicarbonate, followed by water. The organicmixture was dried over sodium sulfate, filtered and concentrated undervacuum to yield 15 (4.16 g, 100%). The benzyl bromide was used as thecrude material without further purification.

[0222]¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, 1H, J=2.0 Hz), 7.30 (dd, 1H,J=2.4 Hz, J=8.4 Hz), 6.85 (d, 1H, J=8.4 Hz), 4.37 (s, 2H), 3.90 (s, 3H).

[0223] General Synthesis of Compound No. 114 in Table II (13)

[0224] a) Reacting 1 with an alkyl halide and base to form 2;

[0225] b) Debenzylation of 2 to form 3;

[0226] c) Alkylation of 3 with a benzyl halide to form 10;

[0227] d) Deprotonation of 10 followed by addition of a brominatingagent to form 11;

[0228] e) Displacement of bromo 11 with an amine to form 12; and

[0229] f) Silyl ether cleavage of 12 to form compound no. 114 in Table11 (13).

[0230] Synthesis of Compound No. 160 in Table II (18)

[0231] Experimental Procedure: Compound No. 160 in Table II (18)

[0232] To 16 (150 mg, 0.579 mmol) was added dimethylformamide (3 mL),6-chloropiperonyl chloride (142 mg, 0.694 mmol) and potassium carbonate(120 mg, 0.868 mmol) under nitrogen. The reaction mixture was stirred atroom temperature for 137 hrs., then diluted with ethyl acetate andwashed with water several times. The organic mixture was dried overmagnesium sulfate, filtered and concentrated under vacuum. Purificationvia PTLC (1/1 ethyl acetate/hexanes) yielded 17 (84.1 mg, 34%).

[0233]¹H NMR (400 MHz, CDCl₃): δ 6.89 (s, 1H), 6.09 (s, 1H), 5.95 (s,2H), 5.59 (s, 2H), 3.60 (s, 3H), 3.38 (s, 3H). HRMS: Calcd forC₁₅H₁₂BrClN₄O₄ (M+H): 426.9809. Found: 426.9802.

[0234] To 17 (72.0 mg, 0.169 mmol) was added cyclohexylamine (86.7 mg,0.883 mmol), diisopropylethylamine (0.8 mL) and 1-methyl-2-pyrrolidinone(0.8 mL). The reaction mixture was heated to 160° C. in a sealed tubefor 17 hrs., then cooled to room temperature. Water was added, then themixture was extracted with ethyl acetate and washed with water severaltimes. The organic mixture was dried over magnesium sulfate, filteredand concentrated under vacuum. Purification via PTLC (1/1 ethylacetate/hexanes) yielded compound no. 160 in Table II (18) (50.9 mg,68%).

[0235]¹H NMR (400 MHz, CDCl₃): δ 6.84 (s, 1H), 6.815 (s, 1H), 5.96 (s,2H), 5.33 (s, 2H), 4.42 (d, 1H, J=7.2 Hz), 3.68-3.79 (m, 1H), 3.53 (s,3H), 3.40 (s, 3H), 1.94-2.05 (m, 2H), 1.55-1.74 (m, 3H), 1.25-1.42 (m,2H), 1.10-1.22 (m, 3H). HRMS: Calcd for C₂₁H₂₄ClN₅O₄ (M+H): 444.2400.Found: 444.2394.

[0236] General Synthesis of Compound No. 160 in Table II (18)

[0237] a) Alkylation of 16 with a benzyl halide to form 17; and

[0238] b) Displacement of bromo 17 with an amine to form compound no.160 in Table II (18).

[0239] Accordingly, the invention includes a method for producing acompound having the formula (I), comprising:

[0240] (i) reacting a compound having the formula (III) with an alkylhalide in the presence of a base to form a compound having the formula(IV):

[0241] where,

[0242] (a) R¹ is a hydrogen atom or a C₁₋₁₅ alkyl group, branched orstraight chain, with or without one or more substituents, a C₂₋₁₅alkenyl group, branched or straight chain, with or without one or moresubstituents, a C₂₋₁₅ alkynyl group, branched or straight chain, with orwithout one or more substituents, a C₃₋₁₅ cycloalkyl group, with orwithout one or more substituents, an arylalkyl group, with or withoutone or more substituents, an aryl group, with or without one or moresubstituents, a heteroaryl group, with or without one or moresubstituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is ahydrogen atom or a hydrocarbon radical, branched or straight-chain, withor without one or more substituents

[0243] (b) L is R² or a protected form of R²; and

[0244] (c) Ph is a phenyl group;

[0245] (ii) debenzylating and then alkylating the compound having theformula (IV) with an alkyl halide, XCH₂R³, to form the compound havingthe formula (V):

[0246] where,

[0247] X is a halogen atom (e.g., a chlorine or bromine atom) and

[0248] R³ is an aryl group, with or without one or more substituents, aheteroaryl group, with or without one or more substituents, or aheterocyclic group having 1 to 3 heteroatoms fused to a 5 or 6 memberedaryl ring, with or without one or more substituents, with the provisothat R³ is not an aryl group substituted at its para position with a—Y-aryl group, where Y is a carbon-carbon single bond, —CO—, —O—, —S—,—N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—,—NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³)(R²⁴)NH—, —CH═CH—,—CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—,

[0249] where,

[0250] R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,C₃₋₆ cycloalkyl, phenyl or benzyl group;

[0251] R²² is a hydrogen atom or a C₁₋₆ alkyl group;

[0252] R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or —CH₂-aryl group;

[0253] R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group;

[0254] R²⁵ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl; C₃₋₆cycloalkyl, phenyl or benzyl group;

[0255] R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenylor benzyl group;

[0256] R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂,

[0257] and

[0258] R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup, or R²⁸ and R²⁹, taken together with each other, are a —(CH₂)_(q)group, where q is 2 or 3;

[0259] wherein, R²¹ through R²⁹ are optionally substituted with any ofthe groups defined above for the one or more substituents; and

[0260] (iii) deprotonating and then halogenating the compound having theformula (V) to form a compound having the formula (VI):

[0261] where,

[0262] Hal is a halogen atom;

[0263] (iv) reacting the compound having the formula (VI) with an aminehaving the formula R⁴NH₂ to form a compound having the formula (VII):

[0264] where,

[0265] R⁴ is a C₃₋₁₅ cycloalkyl group, with or without one or moresubstituents, a C₃₋₁₅ cycloalkenyl group, with or without one or moresubstituents, or a heterocycloalkyl group of 3 to 15 members, with orwithout one or more substituents; and

[0266] (v) removing the protecting portion of L, when L is the protectedform of R², on the compound having the formula (VII) to form thecompound having the formula (I):

[0267] where,

[0268] R² is defined the same as R¹ above, with the proviso that atleast one of R¹ and R² is not a hydrogen atom;

[0269] wherein, the one or more substituents are defined the same as forthe one or more substituents of formula (I) above.

[0270] Pharmaceutically-Acceptable Dosage Forms

[0271] The compounds of the present invention may be administered tohumans or other mammals by a variety of routes, including oral dosageforms and injections (intravenous, intramuscular, intraperitoneal,subcutaneous, and the like). Numerous other dosage forms containing thecompounds of the present invention can be readily formulated by oneskilled in the art, utilizing the suitable pharmaceutical excipients asdefined below. For considerations of patient compliance, oral dosageforms are generally most preferred.

[0272] The rate of systemic delivery can be satisfactorily controlled byone skilled in the art, by manipulating any one or more of thefollowing:

[0273] (a) the active ingredient proper;

[0274] (b) the pharmaceutically-acceptable excipient(s), so long as thevariants do not interfere in the activity of the particular activeingredient selected;

[0275] (c) the type of excipient(s), and the concomitant desirablethickness and permeability (swelling properties) of the excipient(s);

[0276] (d) the time-dependent conditions of the excipient(s);

[0277] (e) the particle size of the granulated active ingredient; and

[0278] (f) the pH-dependent conditions of the excipient(s).

[0279] Pharmaceutically-acceptable excipients include flavoring agents,pharmaceutical-grade dyes or pigments, solvents, co-solvents, buffersystems, surfactants, preservatives, sweetener agents, viscosity agents,fillers, lubricants, glidants, disintegrants, binders and resins.

[0280] Conventional flavoring agents may be used, such as thosedescribed in Remington's Pharmaceutical Sciences, 18^(th) Ed., MackPublishing Co., pp. 1288-1300 (1990), which is incorporated in itsentirety by reference herein. The pharmaceutical compositions of theinvention generally contain from about 0 to 2% of flavoring agents.

[0281] Conventional dyes and/or pigments may also be used, such as thosedescribed in the Handbook of Pharmaceutical Excipients, by the AmericanPharmaceutical Association & the Pharmaceutical Society of GreatBritain, pp. 81-90 (1986), which is incorporated in its entirety byreference herein. The pharmaceutical compositions of the inventiongenerally contain from about 0 to 2% of dyes and/or pigments.

[0282] The pharmaceutical compositions of the invention generallycontain from about 0.1 to 99.9% of solvent(s). A preferred solvent iswater. Preferred co-solvents include ethanol, glycerin, propyleneglycol, polyethylene glycol, and the like. The pharmaceuticalcompositions of the invention may include from about 0 to 50% ofco-solvents.

[0283] Preferred buffer systems include acetic, boric, carbonic,phosphoric, succinic, malaic, tartaric, citric, acetic, benzoic, lactic,glyceric, gluconic, glutaric and glutamic acids and their sodium,potassium and ammonium salts. Particularly preferred buffers arephosphoric, tartaric, citric and acetic acids and salts thereof. Thepharmaceutical compositions of the invention generally contain fromabout 0 to 5% of a buffer.

[0284] Preferred surfactants include polyoxyethylene sorbitan fatty acidesters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolinesters and ethers, alkyl sulfate salts and sodium, potassium andammonium salts of fatty acids. The pharmaceutical compositions of theinvention generally contain from about 0 to 2% of surfactants.

[0285] Preferred preservatives include phenol, alkyl esters ofparahydroxybenzoic acid, o-phenylphenol benzoic acid and salts thereof,boric acid and salts thereof, sorbic acid and salts thereof,chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate andnitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride,methyl paraben and propyl paraben. Particularly preferred preservativesare the salts of benzoic acid, cetylpyridinium chloride, methyl parabenand propyl paraben. The pharmaceutical compositions of the inventiongenerally include from about 0 to 2% of preservatives.

[0286] Preferred sweeteners include sucrose, glucose, saccharin,sorbitol, mannitol and aspartame. Particularly preferred sweeteners aresucrose and saccharin. Pharmaceutical compositions of the inventiongenerally include from about 0 to 5% of sweeteners.

[0287] Preferred viscosity agents include methylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl-methylcellulose,hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia,guar gum, xanthan gum and tragacanth. Particularly preferred viscosityagents are methylcellulose, carbomer, xanthan gum, guar gum, povidone,sodium carboxymethylcellulose, and magnesium aluminum silicate.Pharmaceutical compositions of the invention generally include fromabout 0 to 5% of viscosity agents.

[0288] Preferred fillers include lactose, mannitol, sorbitol, tribasiccalcium phosphate, diabasic calcium phosphate, compressible sugar,starch, calcium sulfate, dextro and microcrystalline cellulose.Pharmaceutical compositions of the invention generally contain fromabout 0 to 75% of fillers.

[0289] Preferred lubricants/glidants include magnesium stearate, stearicacid and talc. Pharmaceutical compositions of the invention generallyinclude from about 0 to 7%, preferably, about 1 to 5% oflubricants/glidants.

[0290] Preferred disintegrants include starch, sodium starch glycolate,crospovidone and croscarmelose sodium and microcrystalline cellulose.Pharmaceutical compositions of the invention generally include fromabout 0 to 20%, preferably, about 4 to 15% of disintegrants.

[0291] Preferred binders include acacia, tragacanth,hydroxypropylcellulose, pregelatinized starch, gelatin, povidone,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,sugar solutions, such as sucrose and sorbitol, and ethylcellulose.Pharmaceutical compositions of the invention generally include fromabout 0 to 12%, preferably, about 1 to 10% of binders.

[0292] Additional agents known to a skilled formulator may be combinedwith the compounds of the invention to create a single dosage form.Alternatively, additional agents may be separately administered to amammal as part of a multiple dosage form.

[0293] For preparing pharmaceutical compositions containing theinventive compounds, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to 95 weightpercent of active ingredient. Suitable solid carriers are known in theart, for example, magnesium carbonate, magnesium stearate, talc, sugarand lactose. Tablets, powders, cachets and capsules can be used as soliddosage forms suitable for oral administration. Examples ofpharmaceutically-acceptable carriers and methods of manufacture forvarious compositions may be found in Remington's PharmaceuticalSciences, 18^(th) Ed., Mack Publishing Co. (1990), which is incorporatedin its entirety by reference herein.

[0294] Liquid form preparations include solutions, suspensions andemulsions. Common liquid form preparations include water andwater-propylene glycol solutions for parenteral injection or addition ofsweeteners and opacifiers for oral solutions, suspensions and emulsions.Liquid form preparations may also include solutions for intranasaladministration.

[0295] Aerosol preparations suitable for inhalation include solutionsand solids in powder form, which may be combined with a pharmaceuticallyacceptable carrier, such as an inert compressed gas (e.g., nitrogen).

[0296] Also included are solid form preparations that may be converted,shortly before use, to liquid form preparations for either oral orparenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0297] The compounds of the invention may also be deliveredtransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and emulsions and may be included in a transdermalpatch of a matrix or reservoir type as is conventional in the art forthis purpose.

[0298] The preferred mode of administering the compounds of theinvention is oral. Preferably, the pharmaceutical preparation is in aunit dosage form. In such a form, the preparation is subdivided intosuitable sized unit doses containing appropriate quantities of theactive component, for example, an effective amount to achieve thedesired purpose.

[0299] The quantity of active ingredient (compound) in a unit dose ofpreparation may be varied or adjusted from about 0.01 to 4,000 mg,preferably, from about 0.02 to 1,000 mg, more preferably, from about 0.3to 500 mg, and most preferably, from about 0.04 to 250 mg, according tothe particular application. A typical recommended daily dosage regimenfor oral administration can range from about 0.02 to 2,000 mg/day, intwo to four divided doses. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.Typically, pharmaceutical compositions of the invention will beadministered from about 1 to 5 times per day, or alternatively, as acontinuous infusion. Such administration can be used as a chronic oracute therapy. The amount of active ingredient that may be combined withcarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Atypical preparation will contain from about 5 to 95% of active compound(w/w). Preferably, such preparations will contain from about 20 to 80wt. % of active compound.

[0300] The pharmaceutically-acceptable carriers employed in conjunctionwith the compounds of the present invention are used at a concentrationsufficient to provide a practical size to dosage relationship. Thepharmaceutically-acceptable carriers, in total, may comprise from about0.1 to 99.9% by weight of the pharmaceutical compositions of theinvention, preferably, from about 20 to 80% by weight.

[0301] Upon improvement of a patient's condition, a maintenance dose ofa compound, composition or combination of the invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. When thesymptoms have been alleviated to the desired level, treatment shouldcease. Patients may, however, require intermittent treatment on along-term basis upon any recurrence of disease symptoms.

[0302] Specific dosage and treatment regimens for any particular patientmay be varied and will depend upon a variety of factors, including theactivity of the specific compound employed, the age, body weight,general health status, sex and diet of the patient, the time ofadministration, the rate of excretion, the specific drug combination,the severity and course of the symptoms being treated, the patient'sdisposition to the condition being treated and the judgment of thetreating physician. Determination of the proper dosage regimen for aparticular situation is within the skill of the art. The amount andfrequency of the administration of compounds of the invention or theirpharmaceutically acceptable salts may be regulated according to thejudgment of the attending clinician, based on the factors recited above.As a skilled artisan will appreciate, lower or higher doses than thoserecited above may be required.

[0303] For example, it is often the case that a proper dosage level isbased on the weight of the patient. For instance, dosage levels ofbetween about 0.01 and 100 mg/kg of body weight per day, preferably,between about 0.5 and 75 mg/kg of body weight per day, and morepreferably, between about 1 and 50 mg/kg of body weight per day, of theinventive compounds, compositions and salts thereof described herein,are therapeutically useful for the treatment of a variety of biologicaldisorders, particularly, male and female sexual dysfunction. Between twopatients of differing weights, a higher dosage will be used for theheavier patient, all other things being equal.

[0304] The inventive compounds are understood to provide efficacioustreatment of (male) erectile dysfunction, including a reasonable time ofonset upon administration, and a reasonable duration afteradministration. For example, in the treatment of erectile dysfunction, adosage of the inventive compound may be taken about an hour before a sexact is to be undertaken. Particular dosages will work within aboutthirty minutes of their administration. Ideal dosages will affect apatient within about fifteen minutes of their administration. Whilefood, diet, pre-existing conditions, alcohol and other systemicconditions could lengthen the time delay for an inventive drug to workafter its administration, it is understood that optimum dosages incombination with sexual stimulation will result in an efficacious drugtreatment within and for a reasonable amount of time.

[0305] The inventive compounds can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, with pharmaceutically-acceptable solvents, such as water, ethanoland the like, are equivalent to the unsolvated forms for purposes ofthis invention.

[0306] The inventive compounds may form pharmaceutically-acceptablesalts with organic and inorganic acids. Examples of suitable acids forsalt formation are hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in a conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution, such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodiumbicarbonate. The free base forms may differ somewhat from theirrespective salt forms in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

[0307] The invention comprises a compound having the formula (I) or(II), a method for making an inventive compound, a method for making apharmaceutical composition from at least one inventive compound and atleast one pharmaceutically-acceptable carrier, and a method of using oneor more inventive compounds to treat a variety of disorders, symptomsand diseases.

[0308] The inventive compounds and their pharmaceutically-acceptablesalt and neutral compositions may be formulated together with apharmaceutically-acceptable carrier. The resulting composition may beadministered in vivo to mammals, such as men or women, to treat avariety of disorders, symptoms and diseases. For example, the inventivecompounds and compositions may be used to treat diseases of theurogenital system, specifically, male erectile dysfunction (e.g.,impotence) and female sexual dysfunction. Male erectile dysfunction maybe defined as an inability of the male to sufficiently obtain and/orsustain an erection to have intercourse with his mate. In the treatmentof erectile dysfunction, it is believed that the inventive PDE Vinhibitors of formulas (I) and (II) are beneficial therapeutic agentsbecause they elevate cGMP levels in the human body. This actionfacilitates corpus cavernosum smooth muscle relaxation, which providesan increased flow of blood therein and results in an erection. Thismakes the inventive compounds especially useful for treating impotenceand other types of diseases that are affected by cGMP levels.

[0309] Accordingly, another aspect of the invention is a method fortreating erectile dysfunction in a mammal in need of such treatment,comprising administering to the mammal at least one compound having theformula (I) or (II) or a pharmaceutical composition thereof in an amounteffective to ameliorate and/or reduce one or more of the symptomsassociated with erectile dysfunction sufficiently enough so that themammal can complete intercourse with another mammal.

[0310] Introduced in 1998 as the first pill to treat impotence, Viagra®today is the most commonly prescribed medication to treatphysiologically-caused erectile dysfunction (“ED”). Certain patients,however, can experience undesirable side effects while taking Viagra®.For instance, the use of Viagra® is contraindicated to patients who areusing organic nitrates, either regularly or intermittently. Physicians'Desk Reference®, 55^(th) Ed, pp. 2534-37 (2001). Combining Viagra® withnitrates can cause a hypotensive episode or suddenly reduce bloodpressure to dangerous levels, which may cause a heart attack. Id.Accordingly, men who have a heart condition that requires the use ofnitrate drugs should not use Viagra®. Id. It has also been reported thatViagra® can cause a vision side effect by impairing the patient's colordiscrimination (blue/green), causing a “blue-halo” light visualalteration. Id. This side effect is presumably due to inhibition of thePDE VI isoenzyme (found in a retina). Id.

[0311] An advantage of the inventive compounds is that they can beparticularly selective for the PDE V isoenzyme in comparison to othertypes of PDE isoenzymes, such as the PDE VI isoenzyme. It is believedthat this increased selectivity will ameliorate side effects associatedwith the use of Viagra®. In particular, the high selectivity of theinventive compounds should minimize, and may even prevent, theoccurrence of a “blue-halo” light visual alteration. It is believed thatthe increased isoenzyme selectivity in inhibiting PDE V isoenzyme (foundin a penis) versus PDE VI isoenzyme (found in a retina) accounts forobviating the “blue-halo” visual side effect.

[0312] Furthermore, a representative inventive compound did notadversely react with nitrate medication in a rat. It is believed thesame lack of adverse interaction will apply to all inventive compoundsin all mammals, including humans. An adverse reaction with nitratemedication may be dangerous and fatal. Adverse reactions include anyreaction that could jeopardize or otherwise diminish the body'sphysiological functions. More specifically, in the case of combinationtherapy for a patient, comprising administering to the patient a nitratedonating agent combined with a PDE V inhibitor agent, an adverse nitratereaction would be one in which the patient's blood pressure dropssignificantly more than with either agent administered alone.

[0313] This feature opens up a method of erectile dysfunction treatmentto many patients who suffer from both an erectile dysfunction and acardiovascular or other disease(s) that is treated with a nitratedonating medicament. Patients suffering from two or more differentailments that require dual (or multiple) treatments may have been bornwith one or both ailments, or later developed one or both ailments dueto genetics or some other type of injury or disease, such as nervedamage, spinal cord injury, diabetes, and the like. Accordingly, it isanother embodiment of this invention to treat a patient suffering fromboth (1) an erectile dysfunction and (2) at least one condition that canbe treated with a nitrate donor medication, the inventive treatmentcomprising, a combination therapy comprising, an administration to amammal of at least one inventive compound or a pharmaceuticalcomposition thereof, and at least one nitrate donating compound or apharmaceutical composition thereof. The patient suffering from botherectile dysfunction and a need for a nitrate donating medicament can betreated for both conditions sequentially, concurrently and/orsimultaneously. The combination therapy can be taken separately in anyform, preferably in oral or patch doses, or can be formulated togetherfor a single, combined dosage.

[0314] The compounds of the present invention may be employed alone orin combination with other agents, particularly, other types of PDEinhibitors (especially cGMP PDE V inhibitors), prostanoids, α-adrenergicreceptor, dopamine receptor agonists, melanocortin receptor agonists,endothelin receptor antagonists, endothelin converting enzymeinhibitors, angiotensin II receptor antagonists, angiotensin convertingenzyme inhibitors, neutral metalloendopeptidase inhibitors, renininhibitors, serotonin 5-HT_(2c) receptor agonists, nociceptin receptoragonists, rho kinase inhibitors, potassium channel modulators andinhibitors of multidrug resistance protein 5.

[0315] Examples of therapeutic agents that may be used in combinationwith compounds of the invention are the following: PDE V inhibitors,such as sildenafil citrate (Viagra®, Pfizer, Connecticut, UnitedStates), Vardenafil™ (Bayer, Germany) and IC-351 (Cialis™, Lilly-ICOS,Washington and Indiana, United States); prostanoids, such asprostaglandin E₁; α-adrenergic agonists, such as phentolamine mesylate;dopamine receptor agonists, such as apomorphine; angiotensin IIantagonists, such as losartan, irbesartan, valsartan and candesartan;and ET_(A) antagonists, such as bosentan and ABT-627.

[0316] It is understood that other combinations may be undertaken whileremaining within the scope of the invention. While one or more of theinventive compounds may be used in an application of monotherapy totreat erectile dysfunction, they also may be used in combinationtherapy, in which the inventive compounds are combined with one or moreother pharmaceutical compounds that are useful for treating erectiledysfunction and/or other types of disorders, symptoms and diseases.

[0317] As discussed above, due to their cGMP-PDE V inhibitoryactivities, the inventive compounds are useful for treating urologicaldisorders, in particular, female and male sexual dysfunctions. Otherphysiological disorders, symptoms and diseases can also benefit fromcGMP-PDE V inhibition. More specifically, the inventive compounds, saltsand derivatives thereof may be used to treat cardiovascular andcerebrovascular diseases, angina pectoris, hypertension, restenosis postangioplasty, endarterectomy, stent introduction, peripheral vasculardiseases, cerebral stroke, respiratory tract disorders, such asreversible airway obstruction, chronic asthma and bronchitis, allergicdisorders associated with atopy, such as urticaria, eczema, and rinitis,pulmonary hypertension, ischemic heart diseases, impaired glucosetolerance, diabetes and related complications, insulin resistancesyndrome, hyperglycemia, polycystic ovarian syndrome, glomerulardiseases, renal insufficiency, nephritis, tubular interstitial disease,autoimmune diseases, glaucoma, intestinal motility disorders, cachexiaand cancer.

[0318] Another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically-acceptable carriers to treatdisorders, symptoms and diseases where cGMP-PDE V inhibition plays arole.

[0319] It is understood that other combinations may be undertaken whileremaining within the scope of the invention. While one or more of theinventive compounds may be used in an application of monotherapy totreat erectile dysfunction, they also may be used in combinationtherapy, in which the inventive compounds are combined with one or moreother pharmaceutical compounds that are useful for treating erectiledysfunction and/or other types of disorders, symptoms and diseases.

[0320] As discussed above, due to their cGMP-PDE V inhibitoryactivities, the inventive compounds are useful for treating urologicaldisorders, in particular, female and male sexual dysfunctions. Otherphysiological disorders, symptoms and diseases can also benefit fromcGMP-PDE V inhibition. More specifically, the inventive compounds, saltsand derivatives thereof may be used to treat cardiovascular andcerebrovascular diseases, angina pectoris, hypertension, restenosis postangioplasty, endarterectomy, stent introduction, peripheral vasculardiseases, cerebral stroke, respiratory tract disorders, such asreversible airway obstruction, chronic asthma and bronchitis, allergicdisorders associated with atopy, such as urticaria, eczema, and rinitis,pulmonary hypertension, ischemic heart diseases, impaired glucosetolerance, diabetes and related complications, insulin resistancesyndrome, hyperglycemia, polycystic ovarian syndrome, glomerulardiseases, renal insufficiency, nephritis, tubular interstitial disease,autoimmune diseases, glaucoma, intestinal motility disorders, cachexiaand cancer.

[0321] Another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically-acceptable carriers to treatdisorders, symptoms and diseases where cGMP-PDE V inhibition plays arole.

[0322] The above description is not intended to detail all modificationsand variations of the invention. It will be appreciated by those skilledin the art that changes can be made to the embodiments described abovewithout departing from the inventive concept. It is understood,therefore, that the invention is not limited to the particularembodiments described above, but is intended to cover modifications thatare within the spirit and scope of the invention, as defined by thelanguage of the following claims.

What is claimed is:
 1. A compound, including an enantiomer,stereoisomer, rotomer, tautomer and/or prodrug thereof, or apharmaceutical composition thereof, the compound having the formula (I):

where, (a) R¹ and R² are, independently of one another, each a C₁₋₁₅alkyl group, branched or straight chain, with or without one or moresubstituents, a C₂₋₁₅ alkenyl group, branched or straight chain, with orwithout one or more substituents, a C₂₋₁₅ alkynyl group, branched orstraight chain, with or without one or more substituents, a C₃₋₁₅cycloalkyl group, with or without one or more substituents, an arylalkylgroup, with or without one or more substituents, an aryl group, with orwithout one or more substituents, a heteroaryl group, with or withoutone or more substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where,R⁵ is a hydrogen atom or a hydrocarbon radical, with or without one ormore substituents, or one of R¹ and R² is a hydrogen atom and the otherone of R¹ and R² is defined the same as above; (b) R³ is an aryl group,with or without one or more substituents, a heteroaryl group, with orwithout one or more substituents, or a heterocyclic group having 1 to 3heteroatoms fused to a 5- or 6-membered aryl ring, with or without oneor more substituents, with the proviso that R³ is not an aryl groupsubstituted at its para position with a —Y-aryl group, where, Y is acarbon-carbon single bond, —CO—, —O—, —S—, —N(R²¹)—, —CON(R²²)—,—N(R²²)CO—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—, —NHC(R²³)(R²⁴)—, —NR²³SO₂—,—SO₂NR²³—, —(R²³)(R²⁴)NH—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—,—CF₂CF₂—,

where, R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,C₃₋₆ cycloalkyl, phenyl or benzyl group; R²² is a hydrogen atom or aC₁₋₆ alkyl group; R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or—CH₂-aryl group; R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group; R²⁵ is ahydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl, C₃₋₆ cycloalkyl,phenyl or benzyl group; R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl or benzyl group; R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂,—NHCSNH₂,

and R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup or, taken together with each other, a —(CH₂)_(q) group, where q is2 or 3; and (c) R⁴ is a C₃₋₁₅ cycloalkyl group, with or without one ormore substituents, a C₃₋₁₅ cycloalkenyl group, with or without one ormore substituents, or a heterocycloalkyl group of 3 to 15 members, withor without one or more substituents; wherein, the one or moresubstituents for all the groups are chemically-compatible and are,independently of one another, each an: alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl,heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl,thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl,mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino,alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino,—COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹),═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹),—N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where: R⁵⁰,R⁵¹ and R⁵² are, independently of one another, each a hydrogen atom or abranched or straight-chain, optionally substituted, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocycloalkyl, heteroaryl or aryl group, or R⁵⁰ andR⁵¹ are joined together to form a carbocyclic or heterocyclic ringsystem, or R⁵⁰, R⁵¹ and R⁵² are, independently of one another, each:

where, R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogenatom or a branched or straight-chain, optionally substituted, alkyl,cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl,heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy,aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono-, di- ortrihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino,phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl,alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl,carboxyalkyl, oximino, —COOR⁵⁰, —COR⁵⁰, —SO⁰⁻²R⁵⁰, —SO₂NR⁵⁰R⁵¹,—NR⁵²SO₂R⁵⁰, —CON(R⁵⁰R⁵¹), —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰,—N(R⁵²)CON(R⁵⁰R⁵¹) or —OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵² aredefined the same as above; R⁴² is a hydrogen atom or a branched orstraight-chain, optionally substituted, alkyl, alkenyl, arylalkyl oracyl group; and R⁴³ is a hydrogen atom or a branched or straight-chain,optionally substituted, alkyl or aryl group; wherein, the optionalsubstituents are defined the same as above for the one or moresubstituents.
 2. The compound or pharmaceutical composition according toclaim 1, where, R¹ is an alkyl or aryl group, with or without the one ormore substituents.
 3. The compound or pharmaceutical compositionaccording to claim 2, where, R¹ is a methyl, ethyl or benzyl group, withor without the one or more substituents.
 4. The compound orpharmaceutical composition according to claim 1, where, R² is an alkylgroup, with or without the one or more substituents.
 5. The compound orpharmaceutical composition according to claim 4, where, R² is a methyl,ethyl, iso-butyl or hydroxyethyl group, with or without the one or moresubstituents.
 6. The compound or pharmaceutical composition according toclaim 1, where, R³ is an aryl group, with or without the one or moresubstituents.
 7. The compound or pharmaceutical composition according toclaim 6, where, R³ is a hydroxyaryl, alkoxyaryl or aminosulfonylarylgroup, with or without the one or more substituents.
 8. The compound orpharmaceutical composition according to claim 7, where, the hydroxyaryl,alkoxyaryl or aminosulfonylaryl group for R³ is substituted with atleast one halogen atom on the aryl ring.
 9. The compound orpharmaceutical composition according to claim 1, where, R⁴ is acycloalkyl or heterocycloalkyl group, with or without the one or moresubstituents.
 10. The compound or pharmaceutical composition accordingto claim 9, where, R⁴ is a cyclohexyl, hydroxycyclopentyl ortetrahydropyranyl group, with or without the one or more substituents.11. The compound or pharmaceutical composition according to claim 1,where, R¹ is a methyl or ethyl group, R² is a methyl, ethyl orhydroxyethyl group, R³ is a 3-chloro-4-hydroxyphenyl,3-bromo-4-hydroxyphenyl, 3-chloro-4-methoxyphenyl,3-bromo-4-methoxyphenyl, or 4-aminosulfonylphenyl group and R⁴ is acyclohexyl, tetrahydropyranyl or 2(R)-hydroxy-1(R)-cyclopentyl group.12. The compound or pharmaceutical composition according to claim 1,where, R¹ is an alkyl or aryl group, with or without the one or moresubstituents, R² is an alkyl group, with or without the one or moresubstituents, and R³ is a 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,3-bromo-4-hydroxyphenyl, 4-methoxyphenyl, 3-chloro-4-methoxyphenyl,3-bromo-4-methoxyphenyl, 4-aminosulfonylphenyl,3-chloro-4-aminosulfonylphenyl or 3-bromo-4-aminosulfonylphenyl group.13. The compound or pharmaceutical composition according to claim 1,which is:


14. The compound or pharmaceutical composition according to claim 1,which is:


15. The compound or pharmaceutical composition according to claim 1,which is:


16. The compound or pharmaceutical composition according to claim 1,which is:


17. The compound or pharmaceutical composition according to claim 1,which is:


18. The compound or pharmaceutical composition according to claim 1,which is:


19. The compound or pharmaceutical composition according to claim 1,


20. The compound or pharmaceutical composition according to claim 1,which is:


21. The compound or pharmaceutical composition according to claim 1,which is:


22. The compound or pharmaceutical composition according to claim 1,which is:


23. The compound or pharmaceutical composition according to claim 1,which is:


24. The compound or pharmaceutical composition according to claim 1,which has a PDE V IC₅₀ within the range of up to about 5 nM.
 25. Thecompound or pharmaceutical composition according to claim 1, which has aratio of PDE VI IC₅₀/PDE V IC₅₀ of >about
 140. 26. The compound orpharmaceutical composition according to claim 1, which has a PDE V IC₅₀within the range of up to about 5 nM and a ratio of PDE VI IC₅₀/PDE VIC₅₀ of >about
 140. 27. The compound or pharmaceutical compositionaccording to claim 1, where, R⁴ is:

where, R¹, R² and R³, independently of one another, are each defined thesame as above for the compound of formula (I); R⁹ is a hydrogen atom oran optionally substituted, oximino, carboxyalkyl, C₁₋₆ alkoxy C₁₋₆ alkylgroup, aryloxy C₁₋₆ alkyl, C₃₋₆ cycloalkoxy C₁₋₆ alkyl, heteroaryloxyC₁₋₆ alkyl, —COOH, ester, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆heterocyclic, hydroxy C₁₋₆ alkyl, aryl or heteroaryl group; R¹⁰ and R¹¹are substituents on the same or different carbon atoms of the ring and,independently of one another, are each: (a) defined the same as abovefor R⁹; (b) a hydroxy group or an ester group derived from a hydroxygroup with a (i) C₁₋₆ carboxylic acid; (ii) C₃₋₆ cycloalkyl C₁₋₆carboxylic acid; (iii) aryl C₁₋₆ carboxylic acid; or (iv) heteroarylC₁₋₆ carboxylic acid group; or (c) a C₁₋₆ alkoxy, amino, C₁₋₆ mono- ordialkylamino, C₁₋₆ alkylacylamino, C₁₋₆ alkylsulfonylamino or—NHCON(R¹⁴)₂ group, with or without one or more substituents, where R¹⁴is a hydrogen atom or an optionally substituted, alkyl or aryl group, orR¹⁰ and R¹¹, taken together with each other and, optionally, with one ormore carbon and/or hetero atoms of the ring, form an optionallysubstituted, spiro- or linearly fused, bi- or tri-cyclic ring system offrom 8 to 12 members, including from 0 to 4 hetero atoms; m and n,independently of one other, are each from 1 to 3; and X is achemically-compatible group, which is —C(R¹⁰R¹¹)—, —S(O)_(y), —O—,—N(R⁶⁰)—, where: R¹⁰ and R¹¹ are defined the same as above; y is from 0to 2; and R⁶⁰ is a hydrogen atom or an optionally substituted, C₁₋₈alkyl, C₁₋₈ alkynyl, C₁₋₈ alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl,C₄₋₈ heterocycloalkyl, COR⁶¹, SO₂R⁶¹, COOR⁶¹, CONR⁶¹R⁶² or SO₂NR⁶¹R⁶²group, where: R⁶¹ is a hydrogen atom or an optionally substituted, C₁₋₈alkyl, C₂₋₈ alkynyl, C₂₋₈ alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl orC₄₋₈ heterocyclic group; and R⁶² is a hydrogen atom or an optionallysubstituted, C₁₋₈ alkyl, C₂₋₈ alkynyl, C₂₋₈ alkenyl, C₃₋₈ cycloalkyl,aryl, heteroaryl or C₄₋₈ heterocyclic group; and when R⁶¹ and R⁶² arethe same or different alkyl groups, they are, optionally, joinedtogether to form a carbocyclic or heterocyclic ring system; wherein, theoptional substituents are defined the same as for the one or moresubstituents of formula (I) above.
 28. The compound or pharmaceuticalcomposition according to claim 27, where, R³ is an optionallysubstituted, hydroxyaryl, alkoxyaryl or aminosulfonylaryl group,wherein, the optional substituents are defined the same as for the oneor more substituents of formula (I) above.
 29. The compound orpharmaceutical composition according to claim 27, where, R⁹ is ahydrogen atom.
 30. The compound or pharmaceutical composition accordingto claim 27, where, one of R¹⁰ and R¹¹ is a hydrogen atom, and the otherone of R¹⁰ and R¹¹ is a hydrogen atom or a hydroxy group.
 31. A methodfor treating a physiological disorder, symptom or disease in a patient,comprising administering to the patient an effective amount of thecompound or pharmaceutical composition according to claim 1, wherein thephysiological disorder, symptom or disease is urogenital,cardiovascular, cerebrovascular, peripheral vascular, angina pectoris,hypertension, restenosis post angioplasty, endarterectomy, stentintroduction, cerebral stroke, respiratory tract, allergic associatedwith atopy, pulmonary hypertension, ischemic heart, impaired glucosetolerance, diabetes and its related complications, insulin resistancesyndrome, hyperglycemia, polycystic ovarian syndrome, glomerular, renalinsufficiency, nephritis, tubular interstitial, autoimmune, glaucoma,intestinal motility, cachexia or cancer.
 32. The method according toclaim 31, wherein the physiological disorder is a urogenital disorder.33. The method according to claim 32, wherein the urogenital disorder isan erectile dysfunction.
 34. A method for elevating a cGMP level in apatient in need of the treatment, comprising administering to thepatient an effective amount of the compound or pharmaceuticalcomposition according to claim
 1. 35. A method for treating an erectiledysfunction in a patient in need of the treatment, comprisingadministering to the patient an effective amount of at least one of thecompound or pharmaceutical composition according to claim
 1. 36. Themethod of claim 35, wherein the patient has been, is being and/or willbe treated with a nitrate donating pharmaceutical composition.
 37. Amethod for treating an erectile dysfunction in a patient in need of thetreatment, comprising administering to the patient an effective amountof at least one of the compound or pharmaceutical composition accordingto claim
 27. 38. The method of claim 37, wherein the patient has been,is being and/or will be treated with a nitrate donating pharmaceuticalcomposition.
 39. A method for treating an erectile dysfunction and/oranother symptom, disease or disorder in a patient in need of thetreatment, comprising administering to the patient a combinationtherapy, comprising an effective amount of at least one of the compoundor pharmaceutical composition according to claim 1 and at least onecompound selected from the group consisting of: a prostanoid,α-adrenergic receptor, dopamine receptor agonist, melanocortin receptoragonist, endothelin receptor antagonist, endothelin converting enzymeinhibitor, angiotensin II receptor antagonist, angiotensin convertingenzyme inhibitor, neutral metalloendopeptidase inhibitor, renininhibitor, serotonin 5-HT_(2c) receptor agonist, nociceptin receptoragonist, rho kinase inhibitor, potassium channel modulator and multidrugresistance protein 5 inhibitor.
 40. A method for producing a compoundhaving the formula (I), comprising: (i) reacting a compound having theformula (III) with an alkyl halide in the presence of a base to form acompound having the formula (IV):

where, (a) R¹ is a hydrogen atom or a C₁₋₁₅ alkyl group, branched orstraight chain, with or without one or more substituents, a C₂₋₁₅alkenyl group, branched or straight chain, with or without one or moresubstituents, a C₂₋₁₅ alkynyl group, branched or straight chain, with orwithout one or more substituents, a C₃₋₁₅ cycloalkyl group, with orwithout one or more substituents, an arylalkyl group, with or withoutone or more substituents, an aryl group, with or without one or moresubstituents, a heteroaryl group, with or without one or moresubstituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is ahydrogen atom or a hydrocarbon radical, branched or straight-chain, withor without one or more substituents; (b) L is R² or a protected form ofR²; and (c) Ph is a phenyl group; (ii) debenzylating and then alkylatingthe compound having the formula (IV) with an alkyl halide having theformula XCH₂R³ to form the compound having the formula (V):

where, X is a halogen atom and R³ is an aryl group, with or without oneor more substituents, a heteroaryl group, with or without one or moresubstituents, or a heterocyclic group having 1 to 3 heteroatoms fused toa 5- or 6-membered aryl ring, with or without one or more substituents,with the proviso that R³ is not an aryl group substituted at its paraposition with a —Y-aryl group, where Y is a carbon-carbon single bond,—CO—, —O—, —S—, —N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—,—SCH₂—, —CH₂S—, —NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³)(R²⁴)NH—,—CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—,

where, R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,C₃₋₆ cycloalkyl, phenyl or benzyl group; R²² is a hydrogen atom or aC₁₋₆ alkyl group; R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or—CH₂-aryl group; R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group; R²⁵ is ahydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl; C₃₋₆ cycloalkyl,phenyl or benzyl group; R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl or benzyl group; R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂,—NHCSNH₂,

and R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup, or R²⁸ and R²⁹, taken together with each other, are a —(CH₂)_(q)group, where q is 2 or 3; wherein, R²¹ through R²⁹ are optionallysubstituted with one or more substituents; and (iii) deprotonating andthen halogenating the compound having the formula (V) to form a compoundhaving the formula (VI):

where, Hal is a halogen atom; (iv) reacting the compound having theformula (VI) with an amine having the formula R⁴NH₂ to form a compoundhaving the formula (VII):

where, R⁴ is a C₃₋₁₅ cycloalkyl group, with or without one or moresubstituents, a C₃₋₁₅ cycloalkenyl group, with or without one or moresubstituents, or a heterocycloalkyl group of 3 to 15 members, with orwithout one or more substituents; and (v) removing the protectingportion of L, when L is the protected form of R², on the compound havingthe formula (VII) to form the compound having the formula (I):

where, R² is defined the same as R¹ above, with the proviso that atleast one of R¹ and R² is not a hydrogen atom; wherein, the one or moresubstituents for all the groups are chemically-compatible and are,independently of one another, each an: alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl,heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl,thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl,mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino,alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino,—COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹),═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹),—N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where: R⁵⁰,R⁵¹ and R⁵² are, independently of one another, each a hydrogen atom or aC₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocycloalkyl, heteroaryl and arylgroup, or R⁵⁰ and R⁵¹ are joined together to form a carbocyclic orheterocyclic ring system, or R⁵⁰, R⁵¹ and R⁵² are, independently of oneanother, each:

where R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogenatom or an alkyl, cycloalkyl, heterocycloalkyl, halo, aryl,imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy,heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- ortrihaloalkyl, mono-, di- or trihaloalkoxy, nitro, cyano, alkoxy,hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl,alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, —COOR⁵⁰,—COR⁵⁰, —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵²SO₂R⁵⁰, —CON(R⁵⁰R⁵¹),—OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰, —N(R⁵²)CON(R⁵⁰R⁵¹) or—OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵² are defined the same as above;R⁴² is a hydrogen atom or an alkyl, alkenyl, arylalkyl or acyl group;and R⁴³ is a hydrogen atom or an alkyl or aryl group; where, R⁴⁰ throughR⁴³ and R⁵⁰ through R⁵² are, independently of one another, eachoptionally substituted with any one of the groups defined above for theone or more substituents.